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Pharmacokinetics and Pharmacodynamics of a Chimeric/Humanized Anti-CD3 Monoclonal Antibody, Otelixizumab (TRX4), in Subjects With Psoriasis and With Type 1 Diabetes Mellitus

Wiczling, P., Rosenzweig, M., Vaickus, L., Jusko, W. J. — Mon, 23 Nov 2009 16:05:18 PST

Otelixizumab is an aglycosylated chimeric/humanized monoclonal antibody (mAb) directed to human CD3. This report describes population pharmacokinetics/ pharmacodynamic (PK/PD) modeling of serum otelixizumab concentrations, changes in CD4+ and CD8+ T-cell counts, and modulation and saturation of CD3/T-cell receptors (TCR) (determined by flow cytometry) after IV administration of otelixizumab in subjects with either type 1 diabetes or psoriasis. Otelixizumab PK were monoexponential with Michaelis-Menten elimination. Nonlinearity was manifested at high concentrations (K_m = 0.968 µg/mL). Lymphocyte dynamics were captured by an indirect response model simplified to direct inhibition. In diabetic subjects, the otelixizumab serum concentration producing a 50% decrease in peripheral blood counts was 0.0187 µg/mL for CD4+ T cells and 0.0120 µg/mL for CD8+ T cells. Corresponding values for psoriatic subjects were much lower: 0.000533 for CD4+ T cells and 0.000269 µg/mL for CD8+ T cells. Total (sum of unbound and otelixizumab-bound) CD3/TCR was approximately equal to unbound CD3/TCR, suggesting that there were few otelixizumab-(CD3/TCR) complexes at the T-cell surface. Down-modulation of CD3/TCR was described by direct inhibition. Otelixizumab concentrations producing 50% reduction in free CD3/TCR sites was similar for diabetes and psoriasis, 0.0144 and 0.0162 µg/mL. Integrated PK/ PD models were successfully applied to assess otelixizumab PK and diverse PD responses.

Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual-Acting Angiotensin Receptor-Neprilysin Inhibitor (ARNi)

Mon, 23 Nov 2009 16:05:19 PST

Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) and multiple-dose (50-900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6-4.9 hours), AHU377 (0.5-1.1 hours), and its active moiety, LBQ657 (1.8-3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open-label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC_0- 0.90 [0.82-0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor-NEP inhibitor (ARNi) for hypertension and heart failure.

Population-Based Exposure-Efficacy Modeling of Ustekinumab in Patients With Moderate to Severe Plaque Psoriasis

Zhou, H., Hu, C., Zhu, Y., Lu, M., Liao, S., Yeilding, N., Davis, H. M. — Mon, 23 Nov 2009 16:05:18 PST

Ustekinumab, a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that binds with high affinity to human interleukin-12 and interleukin-23, has demonstrated efficacy in patients with psoriasis. The objective of this study was to perform exposure-response modeling to increase the understanding of reduction in disease severity following treatment with ustekinumab in patients with moderate to severe psoriasis who participate in two phase III studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg (n = 1312; 11 624 Psoriasis Area and Severity Index [PASI] scores) or placebo (n = 665; 3278 PASI scores). Disease severity was assessed using PASI scores. A population mechanism-based exposure-response model of ustekinumab using NONMEM was developed using serum ustekinumab concentrations and PASI scores. The pharmacodynamic response effect was the reduction in PASI score. The placebo effect, although minor, was also integrated into the model. None of the covariate factors evaluated (eg, demographics, baseline disease characteristics, comorbidities) significantly contributed to the between-subject variability in the pharmacodynamic parameters. The developed exposure-response model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate to severe plaque psoriasis. A robust exposure-response relationship has been confirmed for ustekinumab in psoriasis.

Gender Is an Important Determinant of the Disposition of the Loop Diuretic Torasemide

Mon, 23 Nov 2009 16:05:19 PST

Signals from pharmacovigilance studies indicate that women are at higher risk for adverse drug reactions (ADRs) due to diuretics. Despite the long-term use of torasemide, there are few studies investigating gender differences of torasemide pharmacokinetics in the hospital setting. Therefore, torasemide pharmacokinetics were investigated in 90 patients (45 women, 45 men) during steady-state conditions. Torasemide elimination was significantly reduced in women compared with men (eg, body-weight-normalized area under the concentration-time curve: 42.1 ±20.4 vs 30.9 ±10.3 kg•h/L; P <.001). Among the investigated genetic factors [SLC22A11(OAT4), SLCO1B1(OATP1B1), CYP2C9], only the SLCO1B1c.521T>C polymorphism had a significant influence on torasemide pharmacokinetics. Using cell lines expressing OATP1B1, the authors identified torasemide as OATP1B1 substrate (K_m = 6.2 µM) with a significant reduction of uptake by the 521C-variant. Taken together, gender differences in torasemide pharmacokinetics are likely to contribute to a higher rate of ADRs in women, which has, for example, been observed in a German Pharmacovigilance Project with 66% of hospitalizations due to torasemide ADRs occurring in women.

Desirudin Dosing and Monitoring in Moderate Renal Impairment

Nafziger, A. N., Bertino, J. S. — Fri, 13 Nov 2009 14:24:33 PST

Desirudin is a renally eliminated direct thrombin inhibitor approved to prevent venous thromboembolism. Empiric dosage adjustment and activated partial thromboplastin time (aPTT) monitoring in patients with moderate renal impairment are recommended, but supportive data are lacking. The objective of this study was to evaluate appropriate desirudin dosing in moderate renal impairment and the effect of desirudin on aPTT in moderate renal impairment. Desirudin plasma concentration and aPTT data were extracted from 6 studies. Participants with normal renal function or moderate renal impairment (creatinine clearance [ClCr] 31-60 mL/min) were included. Pharmacokinetic and Monte Carlo simulations were done. After administration of desirudin 15 mg every 12 hours subcutaneously (SC) to steady state, peak desirudin concentrations were 35 and 47 nmol/L in the normal and moderate renal function groups, respectively. Monte Carlo simulations found median 2-hour C_max concentrations of 51.7 nmol/L in normal renal function and 52.4 nmol/L in moderate renal impairment. Desirudin exhibits a linear relationship when the square root of desirudin concentration is plotted versus the aPTT ratio (r² = 0.76). These analyses support the dosing of desirudin at 15 mg every 12 hours SC without aPTT monitoring in patients with moderate renal impairment.

A Randomized, Placebo-Controlled Study of the Effects of the p38 MAPK Inhibitor SB-681323 on Blood Biomarkers of Inflammation in COPD Patients

Singh, D., Smyth, L., Borrill, Z., Sweeney, L., Tal-Singer, R. — Fri, 13 Nov 2009 14:24:32 PST

The p38 mitogen-activated protein kinase (MAPK) signaling upregulates inflammation and is known to be increased in chronic obstructive pulmonary disease (COPD). The authors assessed the pharmacology of the novel p38 MAPK inhibitor SB-681323 using blood biomarkers in COPD. Seventeen COPD patients (forced expiratory volume in 1 second 50%-80% predicted) using short-acting bronchodilators participated in a double-blind, double-dummy, randomized, crossover study. Patients received single oral doses of SB-681323 7.5 mg and 25 mg, prednisolone 10 mg and 30 mg, and placebo. Blood was obtained predose and at 1, 2, 6, and 24 hours postdose. Whole-blood sorbitol-induced phosphorylated (p) heat shock protein (HSP) 27 levels as a marker of p38 pathway activation and lipopolysaccharide-induced tumor necrosis factor (TNF)– production were assessed. Both doses of SB-681323, but not prednisolone, significantly ( P < .0001) reduced weighted mean (WM) pHSP27 (0-6 hours) by 58% compared with placebo. WM TNF- production (0-24 hours) was significantly reduced compared with placebo by SB-681323 25 mg (40%, P = .005) and 7.5 mg (33.4%, P = .02), while prednisolone 30 mg and 10 mg caused 81.5% and 58.2% suppression, respectively (both P < .0001). SB-681323 inhibited the p38 MAPK pathway to a greater degree than prednisolone did. SB-681323 inhibited TNF- production. SB-681323 is a potent p38 MAPK inhibitor that potentially suppresses inflammation in COPD.

Pharmacokinetics of Loxapine Following Inhalation of a Thermally Generated Aerosol in Healthy Volunteers

Spyker, D. A., Munzar, P., Cassella, J. V. — Fri, 13 Nov 2009 14:24:32 PST

The objective of this randomized, double-blind, placebo-controlled, dose escalation study was to determine the pharmacokinetic characteristics, safety, and tolerability of single doses of inhaled loxapine aerosol in healthy volunteers. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Fifty participants were randomized to receive 0.625, 1.25, 2.5, 5.0, or 10 mg of loxapine aerosol or placebo. Following inhalation, the t_max median (25%, 75%) was 2 (1, 3) minutes. The loxapine AUC was dose proportional across all doses with slope (90% confidence interval) of log AUC versus log dose = 0.909 (0.832, 0.987). No clinically meaningful changes were noted in hematology results, blood chemistry, vital signs, or respiratory function. The most common adverse events were dizziness, somnolence, and bad taste. The inhalation of Staccato loxapine represents a safe, well-tolerated means for rapidly achieving therapeutic plasma concentrations of loxapine.

Valacyclovir Pharmacokinetics and Exploratory Pharmacodynamics in Young Adults With Epstein-Barr Virus Infectious Mononucleosis

Vezina, H. E., Balfour, H. H., Weller, D. R., Anderson, B. J., Brundage, R. — Fri, 06 Nov 2009 11:21:40 PST

Primary Epstein-Barr virus (EBV) infection often results in infectious mononucleosis and is associated with serious sequelae. No treatment is approved for EBV infection, and an antiviral intervention would be significant. The objectives of this study are to characterize the pharmacokinetics and explore the pharmacodynamics of acyclovir in plasma and oral washings of 8 subjects receiving 7 days of valacyclovir 1500 mg twice daily for EBV infectious mononucleosis. Virologic and clinical responses are assessed over 12 days. Acyclovir is measured by liquid chromatography/ultraviolet detection. EBV DNA is quantitated by TaqMan polymerase chain reaction. NONMEM VI and linear regression are used for data analysis. Acyclovir profiles in plasma and oral washings are consistent with a 1-compartment model. Final model estimates of clearance, volume of distribution, and fraction of acyclovir in oral wash supernatant are 49.9 L/h, 74.1 L, and 1.14%, respectively. The quantity of EBV DNA in oral washings and blood, and the severity of illness, measured by a graded scale, decrease during treatment. After treatment, viral rebound occurs in oral washings but not in blood, and the severity of illness continues to decline. Acyclovir pharmacokinetic parameters do not correlate with response metrics. These results support further studies of valacyclovir for EBV infectious mononucleosis.

Estimating the Contribution of Genes to Variation in Renal Drug Clearance by Active Secretion Using Multiple Data From Clinical Phase I Studies

Fujita, T., Kumagai, Y., Nakahara, I., Ohtani, Y., Majima, M. — Fri, 06 Nov 2009 11:21:39 PST

Antihypertensive Drug Adherence Among 6408 Chinese Patients on Angiotensin-Converting Enzyme Inhibitors in Hong Kong: A Cohort Study

Wong, M. C. S., Jiang, J. Y., Griffiths, S. M. — Fri, 06 Nov 2009 11:21:40 PST

Few studies have addressed the profile of adherence among ethnic Chinese patients. This study evaluated the factors associated with adherence with angiotensin-converting enzyme inhibitors (ACEIs), an increasingly common antihypertensive drug of choice. The authors included all adult patients who were prescribed an ACEI and paid at least 2 consecutive visits to any primary care clinics of one large territory of Hong Kong from January 2004 to June 2007. The determinants of good adherence to ACEI, as defined by a medication possession ratio ≥80%, were evaluated by multivariate regression analysis. From 6408 eligible patients, 88.0% were adherent. Patients attending family medicine specialist clinics (adjusted odds ratio [AOR] = 1.46, 95% confidence interval [CI]: 1.12-1.91, P = .005) and follow-up visitors (AOR = 2.98, 95% CI: 2.49-3.55, P < .001) were significantly more likely and attendees of staff clinics (AOR = 0.48, 95% CI: 0.25-0.94, P = .033) were less likely to be adherent to ACEIs. Patients’ age, gender, socioeconomic status, district of residence, and the number of comorbidities were not found to be associated with good adherence. Adherence-enhancing strategies should therefore be particularly focused on the new visitors (likely to be drug naive), and future research directions should delineate the best health service setting that could facilitate adherence to ACEIs.

A Semi-Mechanistic Model of CP-690,550-Induced Reduction in Neutrophil Counts in Patients With Rheumatoid Arthritis

Gupta, P., Friberg, L. E., Karlsson, M. O., Krishnaswami, S., French, J. — Fri, 30 Oct 2009 09:59:40 PDT

CP-690,550, a selective inhibitor of the Janus kinase family, is being developed as an oral disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). A semi-mechanistic model was developed to characterize the time course of drug-induced absolute neutrophil count (ANC) reduction in a phase 2a study. Data from 264 RA patients receiving 6-week treatment (placebo, 5, 15, 30 mg bid) followed by a 6-week off-treatment period were analyzed. The model included a progenitor cell pool, a maturation chain comprising transit compartments, a circulation pool, and a feedback mechanism. The model was adequately described by system parameters (BASE_h, ktr_h, , and k_circ), disease effect parameters (DIS), and drug effect parameters (k_offand k_D). The disease manifested as an increase in baseline ANC and reduced maturation time due to increased demand from the inflammation site. The drug restored the perturbed system parameters to their normal values via an indirect mechanism. ANC reduction due to a direct myelosuppressive drug effect was not supported. The final model successfully described the dose- and time-dependent changes in ANC and predicted the incidence of neutropenia at different doses reasonably well.

Hypersensitivity Syndrome Induced by Anticonvulsants: Possible Cross-Reactivity Between Carbamazepine and Lamotrigine

Tue, 20 Oct 2009 09:20:20 PDT

A 14-year-old male presents with erythroderma and fever 44 days after carbamazepine intake. Laboratory exams show eosinophilia and elevated liver enzymes, and thoracic imaging reveals interstitial pneumonitis. All symptoms disappear after carbamazepine withdrawal. A patch test to carbamazepine performed 6 weeks after recovery is positive. About 8 months later, the patient exhibits the same clinical and biological picture 52 days after lamotrigine intake. Lamotrigine is stopped and all symptoms disappear. A patch test to LMG is positive. This case illustrates a possible cross-reactivity between carbamazepine and lamotrigine, which are aromatic and nonaromatic anticonvulsants, respectively.

Population Pharmacokinetics of Perphenazine in Schizophrenia Patients From CATIE: Impact of Race and Smoking

Tue, 20 Oct 2009 09:20:19 PDT

The goal of the study was to characterize population pharmacokinetics (PPK) for perphenazine in patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Patients (n = 156) received 8 to 32 mg of perphenazine daily for 14 to 600 days for a total of 421 plasma concentrations measurements. Nonlinear mixed-effects modeling was used to determine PPK characteristics of perphenazine. One- and 2-compartment models with various random effect implementations and mixture distributions were evaluated. Objective function values and goodness-of-fit plots were used as model selection criteria. Age, weight, sex, race, smoking, and concomitant medications were evaluated as covariates. A 1-compartment linear model with proportional error best described the data. The population mean clearance and volume of distribution for perphenazine were 483 L/h and 18 200 L, respectively. Race and smoking status had significant impacts on perphenazine clearance estimates. In addition, the estimated population mean clearance was 48% higher in nonsmoking African Americans than in nonsmoking other races (512 L/h vs 346 L/h). Active smokers eliminated perphenazine 159 L/h faster than nonsmokers in each race. Clearances for smoking African Americans versus smokers in other races were 671 L/h versus 505 L/h, respectively.

Itraconazole and Rifampin Alter Significantly the Disposition and Antihistamine Effect of Ebastine and Its Metabolites in Healthy Participants

Shon, J.-H., Yeo, C.-W., Liu, K.-H., Lee, S.-S., Cha, I.-J., Shin, J.-G. — Mon, 19 Oct 2009 10:44:11 PDT

The present study was performed to elucidate the effects of itraconazole and rifampin on the pharmacokinetics and pharmacodynamics of ebastine, a nonsedative H1 receptor antagonist. In a 3-way crossover sequential design with 2-week washouts, 10 healthy participants were pretreated with itraconazole for 6 days, rifampin for 10 days, or neither. After oral administration of 20 mg ebastine, blood and urine samples were collected for 72 and 24 hours, respectively, and histamine-induced wheal and flare reactions were measured to assess the antihistamine response for 12 hours. Itraconazole pretreatment decreased the oral clearance of ebastine to 10% (P < .001) and increased the AUC of the active metabolite, carebastine, by 3-fold (P < .001). On the other hand, rifampin pretreatment decreased the AUC of carebastine to 15% (P < .001), with an enormous reduction in the oral bioavailability of ebastine and significantly reduced histamine-induced skin reactions. From these results, the disposition of ebastine and carebastine seems to be significantly altered by coadministration of itraconazole or rifampin. The antihistamine response after ebastine dosing would be decreased following rifampin pretreatments.

No Pharmacokinetic Interaction Between Lacosamide and Carbamazepine in Healthy Volunteers

Cawello, W., Nickel, B., Eggert-Formella, A. — Mon, 19 Oct 2009 10:44:10 PDT

Lacosamide is a new antiepileptic drug for adjunctive treatment of adult partial-onset seizures. Two open-label, multiple-dose clinical trials were conducted to evaluate the potential for pharmacokinetic interaction between lacos amide and carbamazepine. The influence of carbamazepine on lacosamide pharmacokinetics (trial A) and lacosamide on carbamazepine pharmacokinetics (trial B) was investi gated in 19 (trial A) and 18 (trial B) healthy male partici pants. Trial A participants received lacosamide 200 mg bid alone and with carbamazepine 200 mg bid. Trial B partici pants received carbamazepine 200 mg bid alone and with lacosamide 200 mg bid. Pharmacokinetic parameters, area under the concentration-time curve during a dosage interval at steady state (AUC_,ss), and maximum steady-state plasma drug concentration during a dosage interval (C_max,ss) of lacos amide, carbamazepine, and carbamazepine-10,11-epoxide were measured and compared for each drug alone and together. The AUC_,ss and C_max,ss point estimates (combined vs sole treatment) showed relative bioavailability of approx imately 100% for both drugs. All 90% confidence intervals of AUC_,ss and C_{max, ss} were within the generally accepted bioequivalence ranges of 80% to 125%. No changes in rate or extent of absorption or terminal half-life were observed. These results suggest that lacosamide and carbamazepine have a low potential for pharmacokinetic drug-drug interac tion in clinical use.

Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

Mon, 19 Oct 2009 10:44:11 PDT

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferonbased therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.

Specific and Pronounced Impacts of Lisinopril and Lisinopril Plus Simvastatin on Erythrocyte Antioxidant Enzymes

Kaminsky, Y., Suslikov, A., Kosenko, E. — Mon, 19 Oct 2009 10:44:11 PDT

Angiotensin-converting enzyme inhibitors are effective at reducing blood pressure, whereas statins decrease plasma cholesterol impeding atherosclerosis. It is hypothesized that these medications may improve blood pressure and serum cholesterol by modifying the antioxidative status and energy metabolism of erythrocytes. In this study, the effects of 2 treatments are compared: lisinopril alone versus lisinopril + simvastatin, on erythrocyte antioxidant and energy metabolic enzymes. Patients with atherosclerosis and moderate hypertension are randomly assigned to receive lisinopril 10 to 20 mg/d or lisinopril 10 to 20 mg/d plus simvastatin 20 mg/d for 24 weeks. Higher catalase activity and lower glutathione peroxidase activity are observed in 94% to 100% patients from both groups after 12 and 24 weeks of treatment. Superoxide dismutase activity is increased significantly only after 24 weeks. No changes of glutathione reductase, lactate dehydrogenase, and phosphofructokinase activities are found under any conditions indicated. Both treatments decrease systolic and diastolic blood pressure equally. Only lisinopril + simvastatin treatment decreases plasma total cholesterol and low-density lipoprotein cholesterol. The results show for the first time that lisinopril monotherapy and combined lisinopril + simvastatin therapy exhibit specific and pronounced effects on antioxidant and energy metabolic enzyme activities in erythrocytes of hypertensive patients.

Effect of Age, Weight, and CYP2C19 Genotype on Escitalopram Exposure

Mon, 19 Oct 2009 10:44:12 PDT

The purpose of this study was to characterize escitalopram population pharmacokinetics (PK) in patients treated for major depression in a cross-national, US-Italian clinical trial. Data from the 2 sites participating in this trial, conducted at Pittsburgh (United States) and Pisa (Italy), were used. Patients received 5, 10, 15, or 20 mg of escitalopram daily for a minimum of 32 weeks. Nonlinear mixed effects modeling was used to model the PK characteristics of escitalopram. One- and 2-compartment models with various random effect implementations were evaluated during model development. Objective function values and goodness-of-fit plots were used as model selection criteria. CYP2C19 genotype, age, weight, body mass index, sex, race, and clinical site were evaluated as possible covariates. In total, 320 plasma concentrations from 105 Pittsburgh patients and 153 plasma concentrations from 67 Pisa patients were available for the PK model development. A 1-compartmental model with linear elimination and proportional error best described the data. Apparent clearance (CL/F) and volume of distribution (V/F) for escitalopram without including any covariates in the patient population were 23.5 L/h and 884 L, respectively. CYP2C19 genotype, weight, and age had a significant effect on CL/F, and patient body mass index affected estimated V/F. Patients from Pisa, Italy, had significantly lower clearances than patients from Pittsburgh that disappeared after controlling for patient CYP2C19 genotype, age, and weight. Postprocessed individual empirical Bayes estimates on clearance for the 172 patients show that patients without allele CYP2C19*2 or *3 (n = 82) cleared escitalopram 33.7% faster than patients with heterogeneous or homogeneous *2 or *3 (*17/*2, *17/*3, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, n = 46). CL/F significantly decreased with increasing patient age. Patients younger than 30 years (n = 45) cleared escitalopram 20.7% and 42.7% faster than patients aged 30 to 50 years (n = 84) and older than 50 years of age (n = 43), respectively. CYP2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. These variables may affect patient tolerance of this antidepressant and may provide important information in the effort to tailor treatments to patients’ individual needs.

Systemic Bioavailability of Topical Diclofenac Sodium Gel 1% Versus Oral Diclofenac Sodium in Healthy Volunteers

Kienzler, J.-L., Gold, M., Nollevaux, F. — Mon, 19 Oct 2009 10:44:12 PDT

Systemic bioavailability and pharmacodynamics of topical diclofenac sodium gel 1% were compared with those of oral diclofenac sodium 50-mg tablets. In a randomized, 3-way crossover study, healthy volunteers (n = 40) received three 7-day diclofenac regimens: (A) 16 g gel applied as 4 g to 1 knee 4 times daily (4 g on surface area 400 cm²), (B) 48 g gel applied as 4 g per knee 4 times daily to 2 knees plus 2 g gel per hand applied 4 times daily to 2 hands (12 g on 1200 cm²), and (C) 150 mg oral diclofenac applied as 50-mg tablets 3 times daily. Thirty-nine participants completed all 3 regimens. Systemic exposure was greater with oral diclofenac (AUC_0-24, 3890 ± 1710 ng⋅h/mL) than with topical treatments A (AUC_0-24, 233 ± 128 ng⋅h/mL) and B (AUC_0-24, 807 ± 478 ng⋅h/mL). Oral diclofenac inhibited platelet aggregation, cyclooxygenase-1 (COX-1), and COX-2. Topical diclofenac did not inhibit platelet aggregation and inhibited COX-1 and COX-2 less than oral diclofenac. Treatment-related adverse events were mild and limited to application site reactions with diclofenac sodium gel 1% (n = 4) and gastrointestinal reactions with oral diclofenac (n = 3). Systemic exposure with diclofenac sodium gel 1% was 5- to 17-fold lower than with oral diclofenac. Systemic effects with topical diclofenac were less pronounced.

Influence of Development, HIV Infection, and Antiretroviral Therapies on the Gene Expression Profiles of ABC Transporters in Human Lymphocytes

Fri, 16 Oct 2009 10:40:16 PDT

The efficacy of drugs acting on lymphocytes like anticancer, immunosuppressive, and antiretroviral drugs depends on their intracellular concentrations, which could be modulated by membrane efflux pumps belonging to the ABC transporter superfamily. The gene expression profiles of 6 main ABC transporters (MDR1, MRP1, MRP3, MRP4, MRP5, and BCRP) were established in lymphocytes from birth to adulthood using blood samples from 57 children and 15 adults (34 and 5 HIV-infected, respectively). Gene expression levels were quantified by quantitative RT-PCR. In adults, the MRP1 gene had the highest expression, followed by the MRP5 gene. BCRP and MRP4 genes were significantly higher expressed at birth than after 1 month of life. Neither HIV infection nor antiretroviral therapies modulated the gene expression profiles of ABC transporters. In conclusion, drugs that are substrates of BCRP and MRP4, like zidovudine, may have an altered efficacy in newborns.

Clinical Pharmacokinetics and Exposure-Toxicity Relationship of a Folate-Vinca Alkaloid Conjugate EC145 in Cancer Patients

Fri, 16 Oct 2009 10:40:17 PDT

The clinical pharmacokinetics and exposure-toxicity relationship were determined for EC145, a conjugate of folic acid and the Vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), in cancer patients. EC145 plasma concentration and toxicity data were obtained from a first-in-man phase I study and analyzed by nonlinear mixed effect modeling with NONMEM. EC145 concentration-time profile after intravenous administration was well described by a 2-compartment model with a first-order elimination process from the central compartment. BSA was identified as a significant covariate on EC145 clearance, accounting for 14.6% of interindividual variation on EC145 clearance. Population estimates for the clearance, steady-state volume of distribution, distribution, and elimination half-lives were 56.1 L/h, 26.1 L, 6 minutes, and 26 minutes, respectively. Constipation and peripheral neuropathy were the most common and clinically relevant toxicities. The clearance and area under the concentration-time curve (AUC) were significant predictors for the incidence of EC145-induced constipation but not peripheral neuropathy. In conclusion, EC145 is rapidly distributed and eliminated in cancer patients. BSA is a statistically significant covariate on EC145 clearance, but its clinical relevance remains to be defined. EC145-induced constipation occurs at a higher frequency in the patients with lower EC145 clearance, where the drug exposure tends to be higher.

Interspecies Scaling of Therapeutic Monoclonal Antibodies: Initial Look

Ling, J., Zhou, H., Jiao, Q., Davis, H. M. — Fri, 16 Oct 2009 10:40:16 PDT

The authors evaluated interspecies scaling for the prediction of human clearance of 18 therapeutic monoclonal antibodies (mAbs). Human and monkey/chimpanzee data of 14 mAbs were classified based on the targeted antigens (soluble or membrane bound). Simple allometry and/or a time-invariant method (elementary Dedrick plot) were performed. Results indicate that human clearance might be accurately predicted from monkey data for mAbs targeting soluble receptors or membrane-bound receptors with limited tissue distribution using simplified allometry. The optimal exponents were estimated to be 0.85 or If nonlinearity is anticipated at the human efficacious dose, pharmacokinetic parameters obtained at high doses in animals might not be sufficient for full pharmacokinetic characterization and prediction. Using pre-specified criteria, including predicted human clearance (≤ or > 10 mL/d/kg), simplified allometric scaling might be helpful in predicting the effect of receptor-mediated clearance for mAbs targeting membrane-bound antigens. Furthermore, simplified allometry and an elementary Dedrick plot provide similar results in predicted clearance. Given the significant advantages offered by simplified allometry, it should be used when data are available from only 1 species. When reasonable data from ≥ 3 species are available, traditional allometry should be explored. Overall, clearance prediction is useful for human dose prediction in drug discovery and development.

Laropiprant in Combination With Extended-Release Niacin Does Not Alter Urine 11-Dehydrothromboxane B2, a Marker of In Vivo Platelet Function, in Healthy, Hypercholesterolemic, and Diabetic Subjects

Thu, 15 Oct 2009 09:46:48 PDT

Laropiprant, an antagonist of the PGD₂ receptor, DP1, is effective in reducing the flushing symptoms associated with extended-release (ER) niacin and thereby improves the tolerability of niacin therapy for dyslipidemia. Because PGD₂ has been reported to inhibit platelet aggregation in vitro, it has been speculated that antagonism of DP1 may enhance platelet reactivity. Three clinical studies evaluated the potential effect of laropiprant, with or without coadministration of ER niacin, on in vivo platelet function in healthy subjects and hypercholesterolemic or diabetic subjects by measuring urinary levels of 11-dehydrothromboxane B₂ (11-dTxB₂), a marker of in vivo platelet activation. Following 7 days of multiple-dose administration, coadministration of laropiprant with ER niacin did not increase urinary 11-dTxB₂ levels compared to ER niacin alone in healthy, hypercholesterolemic, or diabetic subjects. In hypercholesterolemic and diabetic subjects, laropiprant did not increase urinary 11-dTxB₂ levels compared to placebo. These results demonstrate that laropiprant does not enhance in vivo platelet reactivity, either alone or in combination with niacin.

Absence of Effect of Telbivudine on Cardiac Repolarization: Results of a Thorough QT/QTc Study in Healthy Participants

Poordad, F., Zeldin, G., Harris, S. I., Ke, J., Xu, L., Mayers, D., Zhou, X.-J. — Thu, 15 Oct 2009 09:46:48 PDT

The effect of telbivudine on cardiac repolarization was evaluated in healthy participants at clinical and supratherapeutic doses. Sixty-two participants were enrolled, stratified by sex, and randomized according to a crossover design among 4 treatment sequences: placebo, a single moxifloxacin 400-mg dose as positive calibrator, and telbivudine 600 and 1800 mg/d for 7 days. Intensive time-matched electrocardiogram measurements and pharmacokinetic sampling were performed at baseline and on day 7 over 24 hours. For telbivudine and moxifloxacin, time-matched, placebo-adjusted change from baseline in QT was calculated and corrected using Fridericia’s formula (QTcF). While moxifloxacin produced the expected significant changes in QTcF, none of the changes in QTcF for either doses of telbivudine exceeded 5 ms, and none of the associated upper 1-sided 95% confidence intervals (CI) exceeded the limit of 10 ms. There was no increase in QTcF with increasing plasma telbivudine. The supratherapeutic dose of telbivudine was well tolerated with a safety profile similar to the clinical dose despite a 3-fold increase in plasma exposure. This study therefore met the criteria for a negative thorough QT study. Telbivudine had no adverse effect on cardiac repolarization in healthy participants, even at supratherapeutic exposure, suggesting a broad safety margin.

Lack of Electrocardiographic Effect of Dexlansoprazole MR, a Novel Modified-Release Formulation of the Proton Pump Inhibitor Dexlansoprazole, in Healthy Participants

Vakily, M., Wu, J., Atkinson, S. N. — Tue, 13 Oct 2009 09:59:59 PDT

The effect of the proton pump inhibitor dexlansoprazole, an enantiomer of lansoprazole, on QT intervals was assessed after oral administration of a modifiedrelease formulation of dexlansoprazole (dexlansoprazole MR). In this randomized, positivecomparator, placebocontrolled, 4period crossover study, 40 healthy participants received single doses of dexlansoprazole MR 90 mg, dexlansoprazole MR 300 mg, moxifloxacin 400 mg, and placebo separated by 5day washout intervals. Twentyfourhour electrocardiograms were obtained at baseline and during each dosing period. The number and percentage of participants experiencing an increase in QT interval from baseline to maximum postdose value were evaluated during each dosing regimen, and pharmacokinetic profiles of dexlansoprazole and moxifloxacin were obtained. The mean maximum Fridericiacorrected QT (QT_cF) intervals were similar for both doses of dexlansoprazole MR and placebo but were significantly greater with moxifloxacin (P ≤ .001). With both doses of dexlansoprazole MR, the placeboadjusted mean change from baseline in QT_cF intervals was <5 ms, and the upper boundaries of the 95% 1sided confidence intervals were <10 ms at all time points. Pharmacokinetic analysis indicated that QT intervals were measured at the time of maximum drug plasma concentration. Neither dexlansoprazole MR 90 mg nor 300 mg prolonged QT_cF intervals in healthy participants. Both doses were well tolerated.

Effect of Thyroid Hormone on the Activity of CYP3A Enzyme in Humans

Tue, 06 Oct 2009 09:36:17 PDT

Thyroid hormones have been shown to reduce the activity and expression of cytochrome P450 (CYP) 3A4 in vitro. The influence of thyroid hormone on drug action via a CYP3A-dependent pathway has not been elucidated in humans. This is the first report showing the effect of thy roid hormone on CYP3A enzyme activity in humans. Ten healthy volunteers participate in this open-label study, in which the pharmacokinetics of midazolam and the urinary ratios of 6 β-hydroxycortisol/free cortisol before and after 2 weeks of oral administration of triiodothyronine were compared. Triiodothyronine administration significantly reduced the area under the concentration–time curve ratios for 1'-hydroxymidazolam/midazolam from 0.36 to 0.25 (P < .05) and urinary ratios of 6 β-hydroxycortisol/ free cortisol from 6.92 to 5.88 (P < .05). These results strongly suggested that thyroid hormone reduced CYP3A activity in human and may influence the pharmacokinetics of concomitant CYP3A substrate drugs.

A Phase I Study to Characterize the Safety, Tolerability, and Pharmacokinetics of Topotecan at 4 mg/m2 Administered Weekly as a 30-Minute Intravenous Infusion in Patients With Cancer

Tue, 06 Oct 2009 09:36:18 PDT

Topotecan pharmacokinetics at higher infusion rates (4 mg/m² over 30 minutes) have not been studied. The authors report a pharmacokinetics and safety study of this dose in advanced cancer patients. Sixteen patients were given a 4-mg/m² topotecan infusion intravenously (IV) over 30 minutes weekly for 3 weeks, repeated every 28 days. Pharmacokinetics were determined after the first dose. Plasma concentrations of total topotecan were measured to derive CL, V, C, t, t_1/2, AUC_0-t, and AUC_0-. Plasma total topotecan concentrations decreased biexponentially, with a mean CL value of 20.6 L/h, V_ss value of 101 L, and t_1/2 value of 5.0 h. Nine significant adverse events (all hematologic) were topotecan related. Grade 3 or less adverse events included anemia, thrombocytopenia, leukopenia, and fatigue. Pharmacokinetics of the 4-mg/m² infusion of topotecan over 30 minutes are comparable to findings from studies of lower and higher doses. Toxicities are similar to previous reports.

Pleiotropic Effects of Atorvastatin on Monocytes in Atherosclerotic Patients

Tue, 06 Oct 2009 09:36:18 PDT

The objective of this study was to investigate the gene expression signature of monocyte/macrophages and the pleiotropic effects of atorvastatin on monocytes in atherosclerotic patients. Forty patients with coronary heart diseases were randomly assigned to double-blind therapy with either 20 or 80 mg per day of atorvastatin. Follow-up visits occurred at weeks 6 and 12, including complete chemistry and lipid analyses and quantification of 14 target genes in monocytes. After 12 weeks of therapy, both groups gained beneficial alterations in lipid profiles. Both groups experienced significant reductions in gene expression of lipoprotein-associated phospholipase A2, CD13, leptin receptor, matrix metalloproteases-1, legumain, and prolyl oligopeptidase after 12 weeks of therapy. Only tumor protein 53 was increased in the atorvastatin 80-mg group. Moreover, nonsignificant interactions between dosage and duration of therapy were found. The pleiotropic effects of statins in atherosclerotic patients include increased expression of genes involved in apoptosis of monocyte/ macrophage, inhibition of inflammatory responses, antioxidant properties, prevention of foam cell formation, and stabilization of atherosclerotic plaques. This property fuels potential clinical significance.

The Effects of a Short Course of Antibiotics on Alvimopan and Metabolite Pharmacokinetics

Thu, 01 Oct 2009 09:58:02 PDT

Alvimopan is a novel, oral, peripherally acting mu-opioid receptor (PAM-OR) antagonist that blocks the effects of opioids on the gastrointestinal tract, without blocking opioid-induced analgesic effects. It is metabolized by gut microflora to an active amide-hydrolysis metabolite, which is equipotent to alvimopan. The objective of this study was to characterize the pharmacokinetics of alvimopan and metabolite before, during, and after administration of a short course of antibiotics in healthy adult participants. Simulations were conducted to determine the feasibility for this study. An open-label, sequential drug interaction study was conducted in 45 participants who received twice-daily dosing of alvimopan with and without ciprofloxacin. Metabolite concentrations were reduced by 99.2% (90% confidence interval: 98.8-99.5) in the presence of ciprofloxacin. The interaction occurred rapidly, and recovery was slow. The interaction may be of relevance for patients with relatively high metabolite plasma concentrations prior to antibiotic administration but of little relevance for patients with little or no plasma metabolite exposure initially. Administration of ciprofloxacin decreased alvimopan C_max by 24%, which is of no clinical relevance. There was no effect of ciprofloxacin on alvimopan trough concentrations or AUC. Alvimopan was well tolerated.

Exposure to Hydroxyurea During Pregnancy in Sickle-{beta} Thalassemia: A Report of 2 Cases

Thu, 01 Oct 2009 09:58:01 PDT

Hydroxyurea, used in the treatment of sickle cell anemia, is a teratogenic drug. However, the potential benefits of the drug far outweigh its risks when the fetus of the patient on hydroxyurea therapy gets exposed to the drug in an unplanned pregnancy. The authors present 2 clinically severe cases of patients with sickle-β thalas semia who became pregnant while on hydroxyurea therapy and delivered healthy babies. Hydroxyurea was stopped after the confirmation of the pregnancy and was restarted after the termination of breastfeeding. Seven cases of fetal exposure to hydroxyurea have been reported among sickle cell anemia patients. More such data are required to confirm the effect of hydroxyurea exposure on the fetus. A planned pregnancy is advised for patients on hydroxyurea therapy. However, exposure to the drug during early pregnancy requires regular monitoring of such patients by ultrasonography and clinical examination.

Pharmacokinetics of Trans-resveratrol Following Repeated Administration in Healthy Elderly and Young Subjects

Thu, 01 Oct 2009 09:58:02 PDT

A Systematic Review and Empirical Analysis of the Relation Between Dose and Duration of Drug Action

Hughes, D. A., Aronson, J. K. — Thu, 01 Oct 2009 09:58:02 PDT

There is a log-linear relation between the dose and duration of action of drugs with single-compartment pharmacokinetics and direct, reversible mechanisms of action. However, it has been suggested that this relation does not extend to drugs whose metabolites are active or slowly eliminated, drugs with saturable kinetics, and drugs with hit-and-run effects. The purpose of this study is to test this hypothesis and to quantify the relationship by way of a systematic review coupled to an empirical analysis. All issues of 4 clinical pharmacology journals from 1980 to 2005 are hand-searched for articles that present pharmacodynamic response versus time curves for 4 or more different doses. Data on duration of action, dose, and area under the plasma concentration versus time curve from zero to infinity (AUC) are abstracted and analyzed by panel data regression modeling, with within-study fixed effects. Duration of drug action is defined as the time during which a pharmacodynamic effect (or response) exceeds a nominal threshold. The generalized models of all observations from 33 publications, with duration of action as the dependent variable and the logarithm of the dose (or AUC) as the explanatory variable, yield significant log-linear relationships. The regressions for individual studies are correctly specified in 27 cases; there are insufficient data for analysis in 10 studies, and a loglinear specification is deemed inappropriate in 6. Analysis of published dose-ranging studies shows that the duration of action of a drug is directly proportional to the logarithm of dose across a wide range of different drugs, extending a result that was previously documented for very few compounds.

Assessment of Nevirapine Bioavailability From Targeted Sites in the Human Gastrointestinal Tract

Wed, 30 Sep 2009 09:02:05 PDT

This study investigated absorption of nevirapine (NVP) from targeted sites of the gastrointestinal tract using remotely activated capsules and gamma scintigraphy. A total of 24 participants were randomized to receive 50 mg NVP orally as a suspension or via remotely activated cap sules for release into the ascending colon. The 24 participants were then rerandomized into parallel groups of n = 8 for drug release into the ileum, jejunum, or descending colon. The mean gastric emptying time of capsules ranged from 0.88 to 3.35 hours. The small intestinal and colon transit time ranged from 4.08 to 7.76 hours and 17.6 to 21.2 hours, respectively, and capsule recovery time ranged from 27.6 to 34.4 hours. The relative bioavailability ratio of NVP in the jejunum was 1.06 (90% confidence interval [CI]: 1.00-1.12) compared to suspension. In the ileum, ascending colon, and descending colon, bioavailability decreased to 0.89 (0.80-0.99), 0.82 (0.71-0.95), and 0.58 (0.22-1.53), respectively. The absorption rate decreased by ~10-fold from the jejunum (3.83 h^–1) to the descending colon (0.338 h^–1), and t_max increased from 2.42 hours (jejunum) to 16.3 hours (descending colon). Overall, NVP is absorbed from all 4 sites of the gastrointestinal tract, and the rate of absorption decreased from the jejunum to the descending colon. Relative bioavailability of NVP was in the order of jejunum > ileum > ascending colon > descending colon.

Effects of Duloxetine on the Pharmacodynamics and Pharmacokinetics of Warfarin at Steady State in Healthy Subjects

Chappell, J., He, J., Knadler, M. P., Mitchell, M., Lee, D., Lobo, E. — Wed, 30 Sep 2009 09:02:06 PDT

This study evaluated the pharmacodynamics and pharmacokinetics of once-daily dosing of warfarin at steady state when taken concomitantly with once-daily doses of duloxetine. Healthy subjects with a stable international normalized ratio (INR) of 1.5 to 2.0 on an individualized fixed dose of warfarin (2-9 mg) in period 1 received daily warfarin and duloxetine (60 mg for 14 days [n = 15] or 60 mg for 4 days, then 120 mg for 10 days [n = 15]) in period 2. Across the 14-day period when warfarin was coadministered with duloxetine, the least squares mean INR changes from baseline (warfarin alone) ranged from –0.05 to +0.07, and the 90% confidence intervals ranged from –0.12 to +0.14. Following coadministration of warfarin with 60 mg duloxetine, but not with 120 mg duloxetine, there was a statistically significant prolongation in bleeding time compared to warfarin alone. For both R- and S-warfarin, the 90% confidence interval for the geometric mean ratios of area under the curve (AUC_,ss) and maximum plasma concentrations (C_max,ss) between warfarin administered alone and with 60 or 120 mg duloxetine were contained within the bioequivalence limits of 0.8 to 1.25. In conclusion, duloxetine had no clinically or statistically significant effect on the pharmacodynamics or pharmacokinetics of warfarin at steady state.

The Safety of H2-Blockers Use During Pregnancy

Tue, 29 Sep 2009 11:46:23 PDT

Little data exist on the safety of H₂-blockers during pregnancy. A computerized database of medications dispensed from 1998 to 2007 to all women registered in the "Clalit" health maintenance organization, in the Southern District of Israel, was linked with computerized databases containing maternal and infant hospitalization records from the district hospital. The following confounders were controlled for: parity, maternal age, ethnic group, maternal diabetes, smoking, and peripartum fever. Also, therapeutic pregnancy termination data were analyzed. A total of 117 960 infants were born during the study period, 84 823 of them (72%) to women registered at Clalit; 1148 of the latter were exposed to H₂-blockers during the first trimester of pregnancy. Exposure to H₂-blockers was not associated with an increased risk for congenital malformations (adjusted odds ratio [OR] = 1.03, 95% confidence interval [CI]: 0.80-1.32); also, no such association was found when therapeutic pregnancy terminations were included in the analysis (adjusted OR = 1.17, 95% CI: 0.93-1.46). Exposure to H₂-blockers was not associated with perinatal mortality, premature delivery, low birth weight, or low Apgar scores.

Effect of the Bile Acid Sequestrant Colesevelam on the Pharmacokinetics of Pioglitazone, Repaglinide, Estrogen Estradiol, Norethindrone, Levothyroxine, and Glyburide

Tue, 29 Sep 2009 11:46:22 PDT

The purpose of this study was to assess effects of colesevelam on the pharmacokinetics of glyburide, levothyroxine, estrogen estradiol (EE), norethindrone (NET), pioglitazone, and repaglinide in healthy volunteers. Six drugs with a potential to interact with colesevelam were studied in open-label, randomized clinical studies. The presence of a drug interaction was concluded if the 90% confidence intervals for the geometric least squares mean ratios of AUC_0-t(AUC_0-48for levothyroxine) and C_maxfell outside the no-effect limits of (80.0%, 125.0%). Concomitant administration of colesevelam had no effect on the AUC_0-tor C_maxof pioglitazone but significantly decreased the AUC_0-tand C_maxof glyburide, levothyroxine, and EE and the C_maxof repaglinide and NET. AUC_0-tand of glyburide and EE, but not repaglinide or NET, were ^Cmax significantly decreased when the drug was given 1 hour before colesevelam. When glyburide, EE, or levothyroxine was given 4 hours before colesevelam, no drug interaction was observed. Although colesevelam has a cleaner drug interaction profile than other bile acid sequestrants, it does interfere with absorption of some drugs. A 4-hour window appears sufficient to eliminate these interactions.

Clopidogrel Before Elective Percutaneous Coronary Intervention

Motovska, Z., Widimsky, P. — Tue, 29 Sep 2009 11:46:21 PDT

The introduction of percutaneous coronary intervention (PCI) substantially changed the treatment of patients with coronary artery disease. Stent thrombosis is the most worrisome early complication in patients undergoing PCI. Therefore, antiplatelet therapy forms an integral component of treatment with intracoronary stent implantation. A multitude of randomized and observational studies have helped identify and define the role of clopidogrel in today’s PCI patient. Although much is known about its use, a number of questions still remain.

Analysis of Drug Interactions Involving Fruit Beverages and Organic Anion-Transporting Polypeptides

Greenblatt, D. J. — Tue, 29 Sep 2009 11:46:22 PDT

Recently there has been speculation regarding prescription drug interactions with fruit beverages through inhibition of drug uptake transport by organic anion transporter polypeptides (OATPs). A review of clinical trials indicates that grapefruit juice (GFJ), orange juice (OJ), and apple juice can reduce oral bioavailability of fexofenadine, potentially reducing pharmacodynamic effects of fexofenadine. However, the clinical importance of the interaction is not clearly established. The effect is diminished by temporal separation of fruit juice and fexofenadine administration. GFJ and OJ substantially reduce oral bioavailability of celiprolol, a beta-blocker not available in the United States. Beyond these two examples, other meaningful drug interactions with fruit beverages via OATP inhibition are not established at the present time.

Effects of Mexiletine, a CYP1A2 Inhibitor, on Tizanidine Pharmacokinetics and Pharmacodynamics

Momo, K., Homma, M., Osaka, Y., Inomata, S.-i., Tanaka, M., Kohda, Y. — Tue, 29 Sep 2009 11:46:22 PDT

The aim of this study was to determine whether mexi letine, a CYP1A2 inhibitor, altered the pharmacokinetics and pharmacodynamics of tizanidine. The pharmacokinetics of tizanidine were examined in an open-label study in 12 healthy participants after a single dose of tizanidine (2 mg) with and without mexiletine coadministration (50 mg, 3 times as a pretreatment for a day and 2 times on the study day). Compared with tizanidine alone, mexiletine coadministration increased the peak plasma concentration (1.8 ± 0.8 vs 5.3 ± 1.8 ng/mL), area under the curve (4.5 ±2.2 vs 15.4 ±6.5 ng⋅h/mL), and the half-life (1.3 ±0.2 vs 1.8 ±0.7 h) of tizanidine, respectively (P < .05). Reduction in systolic blood pressure (–10 ± 8 vs –24 ± 7 mm Hg) and diastolic blood pressure (–10 ±7 vs –18 ±8 mm Hg) after tizanidine administration was also significantly enhanced by coadministration of mexiletine (P < .01). Of the 15 patients treated with tizanidine and mexiletine, 4 suffered tizanidine-induced adverse effects such as drowsiness and dry mouth in the retrospective survey. Present results suggested that coadministration of mexiletine increased blood tizanidine concentrations and enhanced tizanidine pharmacodynamics in terms of reduction in blood pressure and adverse symptoms.

Pharmacokinetics and Safety of Sunitinib Malate in Subjects With Impaired Renal Function

Thu, 24 Sep 2009 09:28:06 PDT

This phase I, open-label, single-dose study evaluates the effects of severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis on the pharmacokinetics, safety, and tolerability of sunitinib and its primary active metabolite, SU12662. Subjects with normal renal function (creatinine clearance > 80 mL/min), severe renal impairment (creatinine clearance < 30 mL/min), and ESRD requiring hemodialysis receive a single dose of sunitinib 50 mg. Serial blood samples are collected for quantification of plasma concentrations using a validated liquid chromatography with tandem mass spectrometry assay. Safety is monitored. Twenty-four subjects complete the study. Pharmacokinetics in subjects with severe renal impairment appear similar to those with normal renal function. Plasma exposure to sunitinib and SU12662 appears lower in subjects with ESRD compared with subjects with normal renal function or severe renal impairment. Single-dose sunitinib 50 mg is well tolerated regardless of renal function. The currently approved starting dose of sunitinib 50 mg on Schedule 4/2 is expected to be appropriate for patients with renal impairment; any subsequent dose modifications should be based on patients’ ability to tolerate treatment.

Pharmacokinetics and Pharmacodynamics of a Bolus and Infusion of Cangrelor: A Direct, Parenteral P2Y12 Receptor Antagonist

Thu, 24 Sep 2009 09:28:06 PDT

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers. Twenty-two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens: a 15-µg/kg bolus followed by a 2-µg/kg/ min infusion or a 30-µg/kg bolus followed by a 4-µg/kg/min infusion. The infusion is continued for 60 minutes, and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters. Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes. Moreover, extensive platelet inhibition is maintained throughout the infusion period with near-full recovery of platelet function within 60 to 90 minutes of terminating the infusion. The effect of high-dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate–induced P-selectin expression; however, no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function. Cangrelor administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function.

Microdose Pharmacokinetics of IDX899 and IDX989, Candidate HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors, Following Oral and Intravenous Administration in Healthy Male Subjects

Zhou, X.-J., Garner, R. C., Nicholson, S., Kissling, C. J., Mayers, D. — Wed, 23 Sep 2009 10:37:52 PDT

IDX899 and IDX989 are new non-nucleoside reversetranscriptase inhibitors (NNRTIs) that exhibit potent inhibition of HIV-1 replication, including NNRTI-resistant mutants. This microdose study investigates the pharmacokinetics and determined oral bioavailability. For each compound, 4 healthy male subjects are randomized to receive via a crossover design a single 100-µg oral and intravenous dose together with 100 nCi of [¹⁴C]-labeled drug. Plasma and urine samples are obtained over a period of 168 hours postdose and analyzed for total, unchanged drug and major metabolites using an accelerator mass spectrometry method. Based on total radioactivity, oral absorption is near complete. For the parent drug, mean absolute bioavailability is 61% and 65% for IDX899 and IDX989, respectively. Both compounds are extensively metabolized especially after oral dosing. Observed terminal phase halflives after oral and intravenous doses range from 4 to 10 hours and are comparable for the 2 compounds. Urine excretion of radioactivity for both compounds is less than 10%. These data show for the first time that IDX899 and IDX989 possess favorable pharmacokinetic properties in humans, including high mean absolute bioavailability and long half-life. IDX899 has been selected based on these initial pharmacokinetic assessments and other criteria as the candidate for further clinical development.

Population Pharmacokinetics of Teduglutide Following Repeated Subcutanenous Administrations in Healthy Participants and in Patients With Short Bowel Syndrome and Crohn's Disease

Tue, 22 Sep 2009 10:42:04 PDT

Teduglutide is a GLP-2 analog currently evaluated for the treatment of short bowel syndrome, Crohn’s disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1-compartment model with a site-specific rate constant of absorption in the abdomen, arm, and thigh was used to assess the PK of teduglutide. Apparent clearance (CL/F) of teduglutide in male participants was approximately 18% higher than that observed in female participants (12.4 vs 10.5 L/h, respectively). Body weight was detected as a significant covariate explaining the volume of distribution of teduglutide. The elimination half-life (t_1/2) of teduglutide was also influenced by the body weight of participants. For a male patient weighing 50 and 90 kg, t_1/2 of teduglutide was 0.897 and 2.99 hours, respectively. Renal and hepatic function of patients did not affect the PK of teduglutide. As a result, no dose adjustment was deemed necessary in patients with altered renal or liver function. The population PK model will help to support adequate drug labeling following SC administrations in patients and determine whether an individualized dosage is required.

Effect of Telithromycin on the Pharmacokinetics and Pharmacodynamics of Oral Oxycodone

Tue, 15 Sep 2009 15:31:10 PDT

The aim of this study is to determine whether the inhibition of CYP2D6 and CYP3A4 enzyme activity with telithromycin affects the pharmacokinetics and pharmacodynamics of orally administered oxycodone in a randomized 2-phase crossover study. Eleven healthy subjects were pretreated with 800 mg of oral telithromycin or placebo for 4 days. On day 3, they ingested 10 mg of immediate-release oxycodone. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 hours, and pharmacodynamic effects were evaluated. Telithromycin increased the area under the plasma concentration-time curve (AUC_0-) of oxycodone by 80% (P <.001) and reduced the AUC_0- of noroxycodone by 46% (P <.001). Most of the pharmacokinetic changes were seen in the elimination phase, with little effect by telithromycin on the peak concentration of oxycodone. Pharmacodynamic effects of oxycodone were modestly enhanced by telithromycin. In conclusion, telithromycin clearly reduces the N-demethylation of oxycodone to noroxycodone by inhibiting the CYP450 3A4 enzyme. The use of telithromycin in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid adverse effects. Reduction of oxycodone dose by 25% to 50% followed by readjustment according to the clinical response might be appropriate.

CYP2C9, CYP2C19, and ABCB1 Genotype and Hospitalization for Phenytoin Toxicity

Fri, 17 Jul 2009 11:01:42 PDT