The Journal of Clinical Pharmacology recent issues

Electroporation as an Efficient Physical Enhancer for Skin Drug Delivery

Tue, 20 Oct 2009 15:51:25 PDT

Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Application of high-voltage pulses to the skin increases its permeability (electroporation) and enables the delivery of various substances into and through the skin. The application of electroporation to the skin has been shown to increase transdermal drug delivery. Moreover, electroporation, used alone or in combination with other enhancement methods, expands the range of drugs (small to macromolecules, lipophilic or hydrophilic, charged or neutral molecules) that can be delivered transdermally. The efficacy of transport depends on the electrical parameters and the physicochemical properties of drugs. The in vivo application of high-voltage pulses is well tolerated, but muscle contractions are usually induced. The electrode and patch design is an important issue to reduce the discomfort of the electrical treatment in humans. This review presents the main findings in the field of electroporation—namely, transdermal drug delivery. Particular attention is paid to proposed enhancement mechanisms and trends in the field of topical and transdermal delivery.

Is a Thorough QTc Study Necessary? The Role of Modeling and Simulation in Evaluating the QTc Prolongation Potential of Drugs

Rohatagi, S., Carrothers, T. J., Kuwabara-Wagg, J., Khariton, T. — Tue, 20 Oct 2009 15:51:25 PDT

Concentration-QT (C-QT) modeling has been conducted for multiple compounds at various stages of development in different therapeutic areas. Data from available single and multiple ascending-dose (SAD/MAD) studies were pooled to construct population C-QT models, with post hoc predictions of concentration from a pharmacokinetic model. All SAD and MAD studies employed a customized robust QTc assessment with time-matched triplicate electrocardiograms and centralized manual QTc reading. Sources of variability were characterized, and the relationship between covariates and model parameters was explored, with a particular emphasis on correction for heart rate and diurnal variation. The results of population prediction of QTc prolongation were compared to available thorough QTc (TQT) study results, and the C-QT model was evaluated to determine whether it could establish the QTc prolongation relationship without the TQT results. Negative TQT study results confirmed negative simulation results from phase I/II C-QT models. Simulations were undertaken to characterize the ability of pooled C-QT modeling to obviate the need for a TQT. C-QT modeling should be implemented as a standard part of modeling and simulation at different phases of drug development and used in conjunction with other data that influence the need and/or the timing of a TQT study.

Exposure-Response Analysis in Patients With Schizophrenia to Assess the Effect of Asenapine on QTc Prolongation

Tue, 20 Oct 2009 15:51:25 PDT

An exposure-response (E-R) analysis using linear mixed effects modeling was conducted on data from a thorough QTc trial for asenapine in 148 patients with schizophrenia. In a parallel design, patients received asenapine 5 mg twice daily (BID) for 10 days (10d) followed by 10 mg BID (6d), asenapine 15 mg BID (10d) followed by 20 mg BID (6d), quetiapine 375 mg BID (for assay sensitivity; 16d) or placebo (16d). Triplicate 12-lead electrocardiograms and concentration measurements were obtained on day -1 (baseline), 1, 10, and 16 at 8 scheduled times on each day. At mean C_max for all asenapine doses, the E-R model predicted that the mean QTcF increase was less than 5 milliseconds, the International Conference on Harmonisation-established threshold for clinical concern. The model predicted a mean increase of 7 to 8 milliseconds for quetiapine. The corresponding upper bounds of the 95% confidence intervals were 7.5 milliseconds and 11.2 milliseconds for asenapine and quetiapine, respectively.

Quantitative Population Pharmacokinetic Analysis of Pravastatin Using an Enterohepatic Circulation Model Combined With Pharmacogenomic Information on SLCO1B1 and ABCC2 Polymorphisms

Ide, T., Sasaki, T., Maeda, K., Higuchi, S., Sugiyama, Y., Ieiri, I. — Tue, 20 Oct 2009 15:51:25 PDT

The aims of this study were to develop a population pharmacokinetic (PPK) model for pravastatin pharmacokinetics with regard to enterohepatic circulation (EHC) and to evaluate effects of polymorphisms in SLCO1B1 and ABCC2 on the pharmacokinetic (PK) profile of pravastatin quantitatively. A total of 636 blood samples from 57 healthy male volunteers were used. The PPK analysis was carried out using nonlinear mixed effect modeling (NONMEM) and validated by a bootstrap analysis. The PK profile of pravastatin was best described by a model of EHC with Erlang's distribution. A covariate analysis revealed that SLCO1B1^*15 significantly influenced relative bioavailability (F_rel); F_rel was increased 1.50- and 1.95-fold in participants heterozygous and homozygous, respectively, for the ^*15 allele in comparison with participants without the allele. No ABCC2 polymorphism was identified as a potential covariate for pravastatin. The bootstrap analysis indicated that the PK profile of pravastatin was adequately described by the proposed PPK model. SLCO1B1^*15 has a significant effect on F_rel, indicating that OATP1B1 is one of the determinants of systemic exposure to pravastatin.

Single- and Multiple-Dose Pharmacokinetics and Dose Proportionality of the Psychotropic Agent Paliperidone Extended Release

Tue, 20 Oct 2009 15:51:25 PDT

Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D₂- and serotonergic 5-HT_2A-receptor antagonist that is registered for the treatment of schizophrenia. The controlled rate of release of paliperidone from the ER formulation is designed to have a slower absorption rate, which results in gradual ascending plasma concentrations with observed maximum plasma concentrations occurring at 24 hours after dosing on the first dosing day. On subsequent treatment days, the ER formulation provides minimal fluctuations in plasma concentrations. Paliperidone is eliminated with a terminal half-life of approximately 24 hours. Steady state is achieved after 4 daily doses. Paliperidone ER exhibits time-invariant pharmacokinetics. It shows a 3.5-fold accumulation upon steady state, mainly caused by the controlled release characteristics of the formulation. Paliperidone ER displays dose proportionality over the dose range of 3 to 15 mg; the 90% confidence intervals of the pairwise dose comparisons are all included in the 80% to 125% bioequivalence limits.

Quantitative Analysis of T-wave Morphology Increases Confidence in Drug-Induced Cardiac Repolarization Abnormalities: Evidence From the Investigational IKr Inhibitor Lu 35-138

Tue, 20 Oct 2009 15:51:25 PDT

This study investigates repolarization changes induced by a new candidate drug to determine whether a composite electrocardiographic (ECG) measure of T-wave morphology could be used as a reliable marker to support the evidence of abnormal repolarization, which is indicated by QT interval prolongation. Seventy-nine healthy subjects were included in this parallel study. After a baseline day during which no drug was given, 40 subjects received an I_Kr-blocking antipsychotic compound (Lu 35-138) on 7 consecutive days while 39 subjects received placebo. Resting ECGs were recorded and used to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and study power for both measures. Lu 35-138 increased the QTc interval with corresponding changes in T-wave morphology as determined by MCS. For subjects taking Lu 35-138, T-wave morphology was a more reliable indicator of I_Kr inhibition than QTcF (² = 20.3, P = .001). At 80% study power for identifying a 5-millisecond placebo-adjusted change from baseline for QTcF, the corresponding study power for MCS was 93%. As a covariate to the assessment of QT interval liability, MCS offered important additive information to the effect of Lu 35-138 on cardiac repolarization.

Acute Hemodynamic Effects of Single-Dose Sildenafil When Added to Established Bosentan Therapy in Patients With Pulmonary Arterial Hypertension: Results of the COMPASS-1 Study

Tue, 20 Oct 2009 15:51:25 PDT

This study investigated the acute pharmacodynamic effects of sildenafil in patients with pulmonary arterial hypertension (PAH) and concomitant bosentan treatment, in view of a mutual pharmacokinetic interaction between the 2 drugs. This prospective, open-label, noncomparative, multicenter, phase II study enrolled 45 patients (≥18 years) with stable PAH (idiopathic, familial, or related to corrected congenital systemic-to-pulmonary shunts, drugs, or toxins) and on bosentan treatment for at least 3 months. Patients underwent right heart catheterization to evaluate the acute hemodynamic effects of (a) inhaled nitric oxide (iNO) and (b) a single oral dose of sildenafil (25 mg). Mean pulmonary vascular resistance (PVR) decreased from baseline following iNO (-15%; 95% confidence limits: -21%, -8%; P = .0001). A statistically significant decrease from baseline in mean PVR was also observed 60 minutes following sildenafil administration (-15%; 95% confidence limits: -21%, -10%; P < .0001). The reduction in PVR following sildenafil was comparable to that resulting from iNO. There were no unexpected safety findings. The pharmacodynamic effect suggests that addition of sildenafil to bosentan treatment can elicit additional hemodynamic benefits. These data represent a rationale for long-term combination studies with the 2 compounds.

Absence of QTc Prolongation in a Thorough QT Study With Subcutaneous Liraglutide, a Once-Daily Human GLP-1 Analog for Treatment of Type 2 Diabetes

Tue, 20 Oct 2009 15:51:25 PDT

The objective of this study was to establish effects of liraglutide on the QTc interval. In this randomized, placebo-controlled, double-blind crossover study, 51 healthy participants were administered placebo, 0.6, 1.2, and 1.8 mg liraglutide once daily for 7 days each. Electrocardiograms were recorded periodically over 24 hours at the end of placebo and highest dosing periods. Four different models for QT correction were used: QTci, as the primary endpoint, and QTciL, QTcF, and QTcB as secondary endpoints. The upper bound of the 1-sided 95% confidence interval for time-matched, baseline-corrected, placebo-subtracted QTc intervals was <10 ms for all 4 correction methods. Moxifloxacin (400 mg) increased QTc intervals by 10.6 to 12.3 ms at 2 hours. There was no concentration-exposure dependency on QTc interval changes by liraglutide and no QTc thresholds above 500 ms or QTc increases >60 ms. The authors conclude that liraglutide caused no clinically relevant increases in the QTc interval.

Valproic Acid Plasma Concentration Decreases in a Dose-Independent Manner Following Administration of Meropenem: A Retrospective Study

Haroutiunian, S., Ratz, Y., Rabinovich, B., Adam, M., Hoffman, A. — Tue, 20 Oct 2009 15:51:25 PDT

Several case reports indicate that carbapenem antibiotics, especially meropenem, may decrease the plasma concentrations of valproic acid (VPA), thus decreasing its therapeutic activity. To investigate the onset, severity, and dose dependency of the interaction between meropenem and VPA, the authors carried out a retrospective evaluation of data collected during 24 months from patients hospitalized in a tertiary medical center. The analysis included 36 patients. VPA mean ± SEM plasma concentration decreased from of 50.8 ± 4.5 µg/mL to 9.9 ± 2.1 µg/mL (P < .001) following meropenem administration. After discontinuation of meropenem, VPA plasma concentrations remained low for 7 days and then gradually increased after 8 to 14 days, reaching values comparable to those before meropenem initiation. Different daily VPA doses showed a similar pattern of decreased VPA concentrations. The mean decrease in individual plasma VPA concentration was 82.1% ± 2.7%. The mean VPA plasma concentration of patients in whom samples were drawn within 24 hours of meropenem initiation was 9.9 ± 3.2 µg/mL. In conclusion, the interaction between meropenem and VPA causes a significant decrease in VPA plasma concentration, apparently within 24 hours. As the therapeutic effects of VPA are plasma concentration dependent, the data suggest that these drugs should not be administered concomitantly.

Population Pharmacokinetic Analysis of Panitumumab in Patients With Advanced Solid Tumors

Fri, 25 Sep 2009 13:54:41 PDT

Panitumumab is a fully human monoclonal antibody targeted to the extracellular domain of human epidermal growth factor receptor (EGFR). A comprehensive population pharmacokinetic model of panitumumab was developed using nonlinear mixed-effects modeling of 1200 patients with advanced solid tumors in 14 clinical studies. The disposition of panitumumab was best described with a 2-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination pathways. For a typical male patient with colorectal cancer (80 kg, 60 years old), the estimates for the linear clearance (CL), the maximum nonlinear clearance (V_max/K_m), the central volume of distribution (V₁), the peripheral volume of distribution (V₂), and the Michaelis-Menten constant (K_m) are 0.273 L/d, 28.4 L/d, 3.95 L, 2.59 L, and 0.426 mcg/mL, respectively. Baseline covariates such as body weight, cancer type, age, sex, and race were studied for their influence on panitumumab pharmacokinetics. Body weight was found to be the most influential covariate on panitumumab exposure, affecting CL, V_max, and V₁. The administration of concomitant chemotherapy (IFL, FOLFIRI, or paclitaxel/carboplatin) or intensity of baseline tumor EGFR expression did not alter the pharmacokinetics of panitumumab. The presence of antipanitumumab antibodies in patients (immunogenicity rate 3.4%) did not appear to affect panitumumab exposure substantially (AUC difference 8%). In support of a new drug application in Japan, the model was used to assess panitumumab pharmacokinetics in Japanese patients compared to other racial groups; there were no significant differences in model-predicted steady-state panitumumab AUC, C_max, or C_min after accounting for the effect of body weight.

Multiple Doses of Sitagliptin, a Selective DPP-4 Inhibitor, Do Not Meaningfully Alter Pharmacokinetics and Pharmacodynamics of Warfarin

Fri, 25 Sep 2009 13:54:41 PDT

Sitagliptin is an orally active, highly selective dipeptidyl peptidase IV (DPP-4) inhibitor for treatment of type 2 diabetes mellitus. This randomized, open-label, 2-part, 2-period crossover study assessed pharmacokinetics/pharmacodynamics of warfarin in the presence/absence of multiple-dose sitagliptin. Twelve participants received treatments A and B separated by >7-day washout: treatment A involved coadministration of sitagliptin 200 mg/d for 11 days (days 1-11) and warfarin 30 mg on day 5, and treatment B involved warfarin 30 mg alone on day 1. R(+) warfarin, S(-) warfarin, and international normalized ratio (INR) were assayed predose and up to 168 hours postdose. The geometric mean ratios (GMRs; warfarin + sitagliptin/warfarin alone) (90% confidence intervals [CIs]) were 0.99 (0.95, 1.03) and 0.95 (0.90, 1.02) for the AUC_0- of R(+) and S(-) warfarin, respectively. GMRs (warfarin + sitagliptin/warfarin alone) (90% CIs) were 0.89 (0.86, 0.93) and 0.89 (0.86, 0.92) for the C_max of R(+) and S(-) warfarin, respectively. INR AUC_{0-168 h} and INR_max GMRs were 1.01 (0.96, 1.06) and 1.08 (1.00, 1.17), respectively. Coadministration of sitagliptin and warfarin was generally well tolerated. Pharmacokinetics (AUC for R(+) and S(-) warfarin) and pharmacodynamics (INR of R(+) or S(-) warfarin) were not meaningfully altered following coadministration of multiple-dose sitagliptin and single-dose warfarin, indicating that no dosage adjustment for warfarin is necessary when coadministered with sitagliptin.

Pharmacokinetics and Pharmacodynamics of the Urotensin-II Receptor Antagonist Palosuran in Healthy Male Subjects

Sidharta, P. N., van Giersbergen, P. L. M., Dingemanse, J. — Fri, 25 Sep 2009 13:54:41 PDT

Palosuran is a new potent and specific antagonist of the human urotensin II (U-II) receptor (UT receptor). This entry-into-humans study evaluated the tolerability and safety, pharmacokinetics, and pharmacodynamics of palosuran in a double-blind, placebo-controlled, single ascending-dose design. Oral doses of 5 to 2000 mg were given to 9 sequential groups of 8 healthy young men (6 on active drug, 2 on placebo) each. At regular intervals, tolerability and safety parameters and plasma levels of palosuran and U-II were determined. Urine was collected to determine excretion of sodium, potassium, creatinine, and palosuran. In this study, palosuran was well tolerated. No serious adverse events or dose-related adverse events were reported. No treatment-related pattern was detected for vital signs, clinical laboratory parameters, or electrocardiography parameters. After rapid absorption, palosuran displayed a plasma concentration-time profile characterized by 2 peaks at approximately 1 and 4 hours after drug administration. The apparent terminal elimination half-life was approximately 20 hours. AUC and C_max values increased proportionally with doses up to 500 mg. Excretion of unchanged palosuran in urine was limited. No consistent effect was found on any of the pharmacodynamic variables measured. The results of this entry-into-humans study warrant further investigation of the therapeutic potential of palosuran.

Anticholinergic Activity of Commonly Prescribed Medications and Neuropsychiatric Adverse Events in Older People

Fri, 25 Sep 2009 13:54:41 PDT

This study sought to determine whether the presence of in vitro anticholinergic activity (AA) among different drugs is associated with reporting of neuropsychiatric adverse events (NPAEs) and whether age affects this relationship. Retrospective case/noncase analyses using Australia's spontaneous Adverse Drug Reaction System (ADRS) database containing 150 475 reports determined crude and adjusted reporting odds ratios (RORs) for NPAEs for 23 drugs with various reported in vitro AA. Covariates were age (treated as a dichotomous variable [≥65 years]), gender, and concomitant use of antipsychotics, benzodiazepines, tricyclic antidepressants, and drugs with recognized inherent anticholinergic properties (anticholinergic drugs). The interaction effect between these covariates and each drug exposure category was examined. Age (≥65 years) has a significant association with greater odds relative to younger age for reporting NPAEs. Drugs with reported significant AA in vitro were not always associated with RORs greater than 1 for reporting NPAEs, highlighting a dissonance between the in vitro AA index and ADRS observations. Significant interactions were observed between age (≥65 years) and exposure to cimetidine, anticholinergic drugs, antipsychotics, and tricyclic antidepressants in modifying odds for reporting NPAEs, reinforcing the need for cautious use and monitoring of drugs with AA in older people.

Quantitative Structure-Property Relationships Modeling to Predict In Vitro and In Vivo Binding of Drugs to the Bile Sequestrant, Colesevelam (Welchol)

Fri, 25 Sep 2009 13:54:41 PDT

Quantitative structure-property relationship (QSPR) models were developed to correlate physicochemical properties of structurally unrelated drugs with extent of in vitro binding to colesevelam, and predicted values were compared with drug exposure changes in vivo following coadministration. The binding of 17 drugs to colesevelam was determined by an in vitro dissolution drug-binding assay. Data from several clinical studies in healthy volunteers to support administration of colesevelam in diabetic patients were also collected along with existing in vivo literature data and compared with in vitro results. Steric, electronic, and hydrophobic descriptors were calculated for test compounds, and univariate and partial least squares regression approaches were used to derive QSPR models to evaluate which of the molecular descriptors correlated best with in vitro binding. A quadrant analysis evaluated the correlation between predicted/actual in vitro binding results and the in vivo data. The in vitro binding assay exhibited high sensitivity, identifying those compounds with a low probability of producing relevant in vivo drug interactions. Drug lipophilicity was identified as the primary determinant of in vitro binding to colesevelam by the final univariate and partial least squares models (R² = 0.69 and 0.98; Q² = 0.48 and 0.59). The in vitro assay and in silico models represent predictive tools that may allow investigators to conduct only informative clinical drug interaction studies with colesevelam.

Bioavailability of Mycophenolate Mofetil and Enteric-Coated Mycophenolate Sodium Is Differentially Affected by Pantoprazole in Healthy Volunteers

Fri, 25 Sep 2009 13:54:41 PDT

The influence of pantoprazole 40 mg twice daily on the bioavailability of a single dose of mycophenolate mofetil 1000 mg or enteric-coated mycophenolate sodium is investigated in healthy volunteers. The plasma concentrations of mycophenolic acid and of the inactive metabolite mycophenolic acid glucuronide are measured by high-performance liquid chromatography. The pharmacokinetic parameters following sole administration are similar for mycophenolate mofetil and enteric-coated mycophenolate sodium except for the time to peak concentration, which is longer in the enteric-coated mycophenolate sodium group. Concomitant treatment with pantoprazole significantly (P < .001) lowers the mycophenolic acid exposure following administration of mycophenolate mofetil. The peak concentrations drop by 57%, and area under the curve decreases from 0 to 12 hours by 27%. In contrast, pantoprazole does not change the pharmacokinetics of enteric-coated mycophenolate sodium. Given that mycophenolic acid exposure correlates with the incidence of biopsy-proven acute rejections in renal transplant recipients, these findings may have clinical implications. Administration of pantoprazole in combination with mycophenolate mofetil could possibly result in an insufficient mycophenolic acid exposure, increasing the risk of treatment failure.

Examination of the Effect of Increasing Doses of Etoricoxib on Oral Methotrexate Pharmacokinetics in Patients With Rheumatoid Arthritis

Fri, 25 Sep 2009 13:54:41 PDT

The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC_0- geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC_0-) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC_0- GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC_0- GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC_0- fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib.

Coadministration of Pioglitazone or Glyburide and Alogliptin: Pharmacokinetic Drug Interaction Assessment in Healthy Participants

Karim, A., Laurent, A., Munsaka, M., Wann, E., Fleck, P., Mekki, Q. — Fri, 25 Sep 2009 13:54:41 PDT

Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a ≥10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy.

The Effect of Raltegravir on the Glucuronidation of Lamotrigine

Fri, 25 Sep 2009 13:54:41 PDT

The authors studied the effect of raltegravir on the pharmacokinetics of the antiepileptic agent lamotrigine. Twelve healthy volunteers (group A) received 400 mg raltegravir twice daily from days 1 to 5. On day 4, a single dose of 100 mg lamotrigine was administered. After a washout period, participants received a second single dose of 100 mg of lamotrigine but now without raltegravir (day 32). In group B, 12 participants received the same treatment as in group A but in reverse order. On days 4 and 32, 48-hour pharmacokinetic curves were drawn. Geometric mean ratios (+90% confidence intervals [CIs]) of lamotrigine area under the plasma concentration-time curve (AUC_0->48) and peak plasma concentration (C_max) for raltegravir + lamotrigine versus lamotrigine alone were 0.99 (0.96-1.01) and 0.94 (0.89-0.99), respectively. The mean ratio of the AUC_0->48 of lamotrigine-2N-glucuronide to lamotrigine was similar when lamotrigine was taken alone (0.35) or when taken with raltegravir (0.36). Raltegravir does not influence the glucuronidation of lamotrigine.

Pharmacokinetics, Safety, and Tolerability of Phentermine in Healthy Participants Receiving Taranabant, a Novel Cannabinoid-1 Receptor (CB1R) Inverse Agonist

Fri, 25 Sep 2009 13:54:41 PDT

This study assessed the potential pharmacokinetic interaction and safety/tolerability of taranabant and phentermine coadministration. This was a randomized, double-blind, 3-panel, fixed-sequence study in healthy participants. Panels A, B, and C evaluated the safety/tolerability of phentermine 15 mg coadministered with taranabant 0.5, 1, and 2 mg for 7 days (panel A) and 28 days (panels B and C). In panels A and C, phentermine 15 mg was administered both with (7 days, panel A; 28 days, panel C) and without (7 days) taranabant 0.5 mg or 2 mg to evaluate pharmacokinetics. The primary endpoint was phentermine AUC_{0-24 h} in panels A and C. Secondary endpoints were changes from baseline in blood pressure and heart rate for all panels. The geometric mean ratios and 90% confidence intervals for phentermine AUC_{0-24 h} in the presence/absence of taranabant 0.5 mg and 2 mg were 1.08 (0.99, 1.17) and 1.04 (0.98, 1.10), respectively. No significant differences in blood pressure and heart rate were observed with any treatment versus placebo. Coadministration of taranabant 0.5 mg, 1 mg, and 2 mg with phentermine was well tolerated with no pharmacokinetic interaction and did not result in meaningful changes in blood pressure or heart rate versus placebo.

Safety and Pharmacokinetics of Multiple Doses of Aclidinium Bromide, a Novel Long-Acting Muscarinic Antagonist for the Treatment of Chronic Obstructive Pulmonary Disease, in Healthy Participants

Fri, 25 Sep 2009 13:54:41 PDT

Systemic exposure to anticholinergics used for chronic obstructive pulmonary disease (COPD) may lead to side effects. This study assessed safety, tolerability, and pharmacokinetics of multiple doses of aclidinium bromide, a novel, long-acting antimuscarinic. Sixteen healthy participants received aclidinium bromide 200, 400, or 800 µg or placebo by dry-powder inhaler for 5 days, with ≥7 days washout. Aclidinium bromide and metabolite pharmacokinetics were assessed. Aclidinium bromide plasma levels were below the lower limit of quantification (LLOQ: 0.05 ng/mL) after 200 µg and in most participants after 400 µg. Plasma levels in all participants were below the LLOQ at all doses, including the highest dose, beyond 1 hour postdose. AUC_0-t and C_max at steady state were, respectively, 0.08 ng·h/mL and 0.12 ng/mL (aclidinium bromide), 0.40 ng·h/mL and 0.14 ng/mL (alcohol metabolite), and 13.47 ng·h/mL and 2.26 ng/mL (acid metabolite). The t_max for aclidinium bromide 800 µg was 15 minutes (first kinetic time point). Adverse event frequency was comparable between treatment groups and placebo. The most commonly reported adverse events, probably treatment related, were coughing (n = 2) and dysphagia (n = 1); 94% of adverse events were mild. These data suggest a low systemic bioavailability and favorable safety profile for aclidinium bromide with repeated dosing for COPD.

Model-Based Evaluation of QTc Interval Risk: An Increasing Emphasis on Early Decision Making

Krishna, R. — Fri, 28 Aug 2009 14:35:31 PDT

Fixed Dosing Versus Body Size-Based Dosing of Monoclonal Antibodies in Adult Clinical Trials

Wang, D. D., Zhang, S., Zhao, H., Men, A. Y., Parivar, K. — Fri, 28 Aug 2009 14:35:31 PDT

Although without clear scientific rationale, body size–based dosing is often used for administering monoclonal antibodies (mAbs). This simulation study compared the performance of body size–based and fixed dosing in reducing pharmacokinetic (PK) and/or pharmacodynamic (PD) variability in adults for 12 mAbs with published population PK and/or PD models. At the population level, 95th percentile intervals of concentration-time profiles, distribution, and variability of exposure for 1000 subjects after both dosing approaches were examined. At the individual level, the difference between the exposures of patients with extreme body sizes from the typical exposure following both approaches was compared. The results show that the 2 dosing approaches perform similarly across the mAbs investigated with fixed dosing being better for some mAbs and body size–based dosing being better for the others. Based on this finding, we recommend using fixed dosing in first-in-human (FIH) adult studies because it offers other advantages. When sufficient data become available, a full assessment of body size effect on PK/PD should be conducted to determine the optimal dosing approach for phase 3 trials. Other factors that may affect the selection of dosing approach were also discussed. Dosing approach for mAbs in the pediatric population is out of the scope of this study.

Human Pharmacokinetics/Pharmacodynamics of an Interleukin-4 and Interleukin-13 Dual Antagonist in Asthma

Burmeister Getz, E., Fisher, D. M., Fuller, R. — Fri, 28 Aug 2009 14:35:31 PDT

Pitrakinra, a 15-kDa recombinant human interleukin-4 mutein, targets allergic Th2 inflammation by competitively binding to interleukin-4 receptor alpha to interfere with interleukin-4 and interleukin-13 action. The authors characterized pitrakinra pharmacokinetics using data from 96 atopic patients, then compared pharmacokinetics with pharmacological response in asthma following subcutaneous versus inhalation dosing. A 1-compartment systemic model with site-specific absorption describes pitrakinra pharmacokinetics following subcutaneous, nebulization, and inhalation powder delivery. Typical CL/F and V/F, referenced to subcutaneous administration, are 15.5 L/h and 67.5 L, yielding a 3.0-hour half-life of plasma decline. Absorption into the blood (half-life ≤1.0 hour, lag ≤18 minutes) is more rapid than elimination. Relative to subcutaneous injection, systemic availability of the first inhaled dose is ≤3%. Subcutaneous injection produced variable efficacy despite high systemic exposure, suggesting inadequate exposure at the site of action in some participants. Inhalation produced consistent pharmacodynamic response despite low systemic exposure. The lung appears as the primary site of pitrakinra's antiasthmatic action, supporting direct administration to the lung for the treatment of asthma.

Steady-State Pharmacokinetics Following Application of a Novel Transdermal Estradiol Spray in Healthy Postmenopausal Women

Morton, T. L., Gattermeir, D. J., Petersen, C. A., Day, W. W., Schumacher, R. J. — Fri, 28 Aug 2009 14:35:31 PDT

This study was designed to evaluate the steady-state pharmacokinetics (PK) of estradiol and its metabolites, estrone and estrone sulfate, following application of a novel estradiol transdermal spray to healthy postmenopausal women. Participants were randomly assigned in parallel to receive 1-, 2-, or 3-spray doses (24 participants/dose level) of a 1.7% estradiol metered-dose transdermal spray (1.53 mg/spray) once daily for 14 days. Blood was collected predose on days 1 to 14 and over 7 days after the last dose. Serum concentrations for all 3 analytes reached steady state by day 7 or 8 and were still slightly above baseline on day 21. Estradiol, estrone, and estrone sulfate serum concentrations generally increased with increasing dose. Mean estradiol and estrone maximum serum concentration (C_max) following 1, 2, or 3 sprays for 14 days were 36 and 50, 57 and 60, and 54 and 71 pg/mL, respectively. Estradiol time when maximum concentration occurred (t_max) was 18 to 20 hours. The area under the serum concentration-time curve over 24 hours following the last dose of study drug (AUC_{0-24 h}) on day 14 for the 1-, 2-, and 3-spray groups, respectively, was 471, 736, and 742 pg·h/mL for estradiol; 886, 1208, and 1367 pg·h/mL for estrone; and 16 501, 26 515, and 27 971 pg·h/mL for estrone sulfate. The metered-dose estradiol transdermal spray delivers estradiol at therapeutic levels and produces low serum estrone concentrations.

Lack of Pharmacokinetic Interactions Between Transdermal Rotigotine and Oral Levodopa/Carbidopa

Braun, M., Cawello, W., Andreas, J.-O., Boekens, H., Horstmann, R. — Fri, 28 Aug 2009 14:35:31 PDT

This open-label phase I trial assessed potential pharmacokinetic interactions between oral levodopa/carbidopa and transdermal rotigotine treatment at steady state. Twenty-four participants with idiopathic restless legs syndrome (12 per group) received levodopa/carbidopa (100 mg/25 mg bid) and rotigotine (initial dose 2 mg/24 h for 3 days, followed by 4 mg/24 h) in a randomized sequence as monotherapy and in combination during hospitalization for 13 days. Primary pharmacokinetic parameters were AUC_ss and C_max,ss of levodopa, carbidopa, and rotigotine at steady state. Mean concentration-time profiles of the 3 agents were similar during monotherapy and combination treatment. The point estimate for the ratio of geometric means (combined vs monotherapy) for AUC_ss and C_max,ss for levodopa (0.98 and 1.04), carbidopa (1.03 and 1.06), and unconjugated rotigotine (1.02 and 0.98) was near unity. All 90% confidence intervals were within the acceptance range for bioequivalence (0.8, 1.25). The most frequently documented adverse events were application site reactions (itching and reddening at application site) and headache. Most adverse events were mild to moderate in intensity, but 2 were of severe intensity (headache and extrasystoles); no serious adverse events occurred. The data presented indicate that rotigotine and levodopa/carbidopa can be coadministered without pharmacokinetic interactions between the compounds.

Population Pharmacokinetics of Golimumab, an Anti-Tumor Necrosis Factor-{alpha} Human Monoclonal Antibody, in Patients With Psoriatic Arthritis

Fri, 28 Aug 2009 14:35:31 PDT

The population pharmacokinetics of subcutaneously administered golimumab (50 mg or 100 mg every 4 weeks) were characterized in patients with active psoriatic arthritis (PsA) in GO-REVEAL, a randomized, double-blind, placebo-controlled, phase 3 study. A total of 2029 serum golimumab concentrations from 337 patients were analyzed using NONMEM. A 1-compartment pharmacokinetic model with first-order absorption and elimination was chosen to describe the observed concentration–time data. For a patient of standard weight (70 kg), the population estimates (typical value ± standard error) for golimumab pharmacokinetic parameters were as follows: apparent clearance = 1.38 ± 0.04 L/d, apparent volume of distribution = 24.9 ± 1.04 L, and absorption rate constant = 0.908 ± 0.121 per day. The between-subject variability was 37.6% in apparent clearance and 37.9% in apparent volume of distribution. Body weight, antibody-to-golimumab status, baseline C-reactive protein level, and smoking status were identified as significant covariates on apparent clearance. Body weight was also a significant covariate on apparent volume of distribution. None of the concomitant medications examined (methotrexate, corticosteroids, and nonsteroidal anti-inflammatory drugs) were significant covariates on apparent clearance, although the median trough golimumab concentration in patients receiving methotrexate was higher than for those not receiving methotrexate. These significant covariates account for part of the variability in systemic exposure to golimumab observed in patients with PsA.

Population Pharmacokinetic Analysis of Linezolid in Patients With Infectious Disease: Application to Lower Body Weight and Elderly Patients

Abe, S., Chiba, K., Cirincione, B., Grasela, T. H., Ito, K., Suwa, T. — Fri, 28 Aug 2009 14:35:31 PDT

Linezolid (Zyvox), belonging to oxazolidinone antibiotics, is commonly used for the treatment of patients infected with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although linezolid has been approved worldwide, the Japanese pharmacokinetic (PK) profile has not been characterized in detail. The objective of this study is to develop a population PK model for linezolid that can be applied to a Japanese population. This population PK model was established based on the 1 Japanese phase III and 4 Caucasian phase II/III studies. A total of 2539 linezolid plasma concentration measurements from 455 patients, aged 18 to 98 years and body weight 30 to 190.5 kg, were used for the analysis. The data were analyzed using nonlinear mixed effects modeling. Body weight (BW), age, ethnicity, and gender were investigated as covariates. The final model was validated by the bootstrap technique. The PK profiles of linezolid were described with a 1-compartment PK model with first-order absorption and first-order elimination. In the final population PK model, BW and age were influential covariates on clearance, and the distribution volume was affected by BW. The present population PK model of linezolid described well the PK profiles in Japanese patients who have lower BW and are relatively older compared with those in the United States/European Union.

Interindividual Variability in Pharmacokinetics of Generic Nucleoside Reverse Transcriptase Inhibitors in TB/HIV-Coinfected Ghanaian Patients: UGT2B7*1c Is Associated With Faster Zidovudine Clearance and Glucuronidation

Fri, 28 Aug 2009 14:35:31 PDT

There are limited data on the pharmacokinetics of generic nucleoside reverse transcriptase inhibitors (NRTIs) in native African populations, in whom they are commonly used. The authors characterized the pharmacokinetics of lamivudine (n = 27), zidovudine (n = 16), and stavudine (n = 11) in human immunodeficiency virus (HIV)/tuberculosis (TB)–coinfected Ghanaians and evaluated associations between zidovudine metabolism and UDP-glucuronosyltransferase (UGT) 2B7 polymorphisms. Lamivudine, zidovudine, and stavudine apparent oral clearance (CL/F) values (mean ± SD [% coefficient of variation [CV]) were 7.3 ± 2.8 (39%), 31.9 ± 33.6 (106%), and 16.4 ± 5.8 (35%) mL/min/kg, respectively, whereas half-life values were 4.2 ± 1.9 (46%), 8.1 ± 7.9 (98%), and 1.5 ± 1.0 (65%) hours, respectively. Zidovudine CL/F was 196% higher (P = .004) in UGT2B7*1c (c.735A>G) carriers versus noncarriers. This was confirmed using human liver bank samples (n = 52), which showed 48% higher (P = .020) zidovudine glucuronidation and 33% higher (P = .015) UGT2B7 protein in UGT2B7*1c carriers versus noncarriers. In conclusion, generic NRTI pharmacokinetics in HIV/TB-coinfected Ghanaians are similar to other populations, whereas the UGT2B7*1c polymorphism may explain in part relatively high interindividual variability in zidovudine clearance.

Abstracts: Thirty-Eighth Annual Meeting American College of Clinical Pharmacology September 13-15, 2009 San Antonio, Texas

Fri, 28 Aug 2009 14:35:31 PDT

Direct-to-Consumer/Patient Advertising of Genetic Testing: A Position Statement of the American College of Clinical Pharmacology

Ameer, B., Krivoy, N. — Tue, 14 Jul 2009 18:01:54 PDT

The In Silico Child: Using Simulation to Guide Pediatric Drug Development and Manage Pediatric Pharmacotherapy

Laer, S., Barrett, J. S., Meibohm, B. — Tue, 14 Jul 2009 18:01:54 PDT

Significant gains have been made in the appreciation of pediatrics as an important population in which rationale pharmacotherapy guidance is warranted but often currently lacking. Although the regulatory framework for major improvements in pediatric drug development was implemented in Europe a decade later than the United States, recent efforts, including the 2007 "Better Medicines for Children" initiative, indicate that the awareness of this problem is indeed a global phenomenon. Nevertheless, there still remains a gap between the awareness and the implementation of rationale and scientifically based drug development and applied pharmacotherapy in children. Specifically, a vision of how best to move from empiricism toward a plan that incorporates biologic knowledge about the maturation of physiologic processes as well as the drug- and disease-specific knowledge generated from drug development and applied pharmacotherapy in adults must evolve from the present intentions. Modeling and simulation approaches can facilitate such a vision that ultimately should provide benefit to pediatric patients. Although recent examples of pediatric in silico approaches are compelling, their ultimate value may be in the identification of data and studies that better guide drug therapy and in the education of pediatric caregivers to the principles of clinical pharmacology that underlie optimal pharmacotherapeutic decisions in children.

Comparison of Semiautomated and Fully Automated Methods for QT Measurement During a Thorough QT/QTc Study: Variability and Sample Size Considerations

Tyl, B., Kabbaj, M., Fassi, B., De Jode, P., Wheeler, W. — Tue, 14 Jul 2009 18:01:54 PDT

This study compares the ability of 2 semiautomated methods with a fully automated method for QT measurement to minimize the sample size required to detect a moxifloxacin effect and exclude a placebo effect in a thorough QT/QTc study. The fully automated and 1 of 2 semiautomated methods used a global QT measurement in 12 leads, whereas the other semiautomated method used a tangent method on single lead raw complexes. Mean QTcF intervals were greater when measured on a global QT electrocardiogram than on raw complexes, but the mean magnitudes of QTcF were similar for all methods. The 3 methods detected a statistically significant increase in QTcF for moxifloxacin compared to placebo and were able to exclude a placebo effect on QTcF in all 62 participants. However, due to a smaller variability, the semiautomated methods allowed these detections with fewer than 20 participants, whereas the fully automated required at least 27 participants.

Pharmacokinetic and Pharmacodynamic Modeling of a Copper-Selective Chelator (TETA) in Healthy Adults

Cho, H.-Y., Blum, R. A., Sunderland, T., Cooper, G. J. S., Jusko, W. J. — Tue, 14 Jul 2009 18:01:54 PDT

The population pharmacokinetics (PK) and pharmacodynamics (PD) of triethylenetetramine (TETA) dihydrochloride (trientine, GC811007) administered orally as 100-, 300-, 600-, or 1800-mg twice-daily doses were assessed in healthy adult male and female volunteers. This study was a randomized, double-blind, placebo-controlled, group-sequential, dose-escalating design. Forty participants, 10 per dose level (8 receiving TETA, 2 receiving placebo), received twice-daily doses for 14 consecutive days. A 2-compartment model for the PK and a linear direct effect model for drug-induced copper excretion (PD) were employed. The population PK/PD model was applied using the NONMEM software. Covariates tested were glomerular filtration rate (GFR), body weight, and gender. Multiple daily doses of TETA were safe and generally well tolerated. The linear 2-compartment model with first-order absorption well characterized the serum concentration data. Although its role was small, GFR had a statistically significant (P < .05) influence on systemic clearance (CL/F). The augmentation of copper excretion was well described by a direct linear model in which the slope was related to GFR and gender (P < .001). The intersubject coefficient of variation was 22.2% for slope (SL) and 82.5% for intercept (ER₀). TETA has consistent single/multiple-dose pharmacokinetics and dose-proportional and serum concentration-proportional effects on enhancing copper excretion.

Effect of 393T>C Polymorphism of GNAS1 Gene on Dobutamine Response in Chinese Healthy Subjects

Tue, 14 Jul 2009 18:01:54 PDT

The purpose of this study was to characterize the functional consequences of the 393T>C polymorphism of the GNAS1 gene in vivo. PCR-RFLP assays were used to identify GNAS1 and β₁-adrenoceptor genotypes. The heart rate (HR), blood pressure, left ventricular fractional shortening (LVFS), and left ventricular ejection fraction (LVEF) were determined in different genotypes through a modified dobutamine stress echocardiography protocol. Our results showed that individuals with homozygous or heterozygous C393 had an increased cardiovascular agonistic response to dobutamine, and the increases from baseline in LVFS at the 3 dosage levels of dobutamine were 19.3% ± 1.0% versus 32.0% ± 2.9%, 36.7% ± 3.1% versus 41.3% ± 4.1%, and 51.7% ± 3.3% versus 58.7% ± 2.6% in T393 homozygotes and C393 homozygotes or heterozygotes, respectively (P = .026). Significant differences were also found between these 2 groups with the increases from baseline in LVEF (P = .007) and SBP (P = .048). In addition, there were significant differences in the increases from atopine in LVFS (P = .011), LVEF (P = .004), and SBP (P = .046) between the T393 homozygotes and C393 homozygotes or heterozygotes. The change of LVEF in C393 homozygous was higher than that in T393 homozygous at the dose of 40 µg/kg/min (28.9% ± 4.0% vs 36.4% ± 2.1%; 95% CI, 18.8%-38.9%; P = .046). These data suggested that the 393T>C polymorphism of GNAS1 was functionally relevant in vivo.

A Thorough QTc Study to Assess the Effect of Sitagliptin, a DPP4 Inhibitor, on Ventricular Repolarization in Healthy Subjects

Tue, 14 Jul 2009 18:01:54 PDT

A randomized, double-blind, placebo-controlled, 4-period crossover study was performed with a single oral dose of sitagliptin (100 mg, 800 mg), moxifloxacin (400 mg), and placebo in order to provide a rigorous assessment of the effect of sitagliptin on ventricular repolarization based on the ICH E14 guidance. The clinical dose of sitagliptin 100 mg was not associated with an increase in QTc interval, corrected using the Fridericia correction (QTcf), at any time point. The supratherapeutic 800-mg dose of sitagliptin was generally well tolerated and was associated with minimal, clinically insignificant prolongation of the QTcf interval at concentrations approximately 11-fold higher than maximal concentrations following the 100-mg clinical dose. The PK/QTc model demonstrated a shallow relationship between the plasma concentration of sitagliptin and the placebo-subtracted QTcf change from baseline, with a 0.59-millisecond increase in QTc for every 1000-nM increment in sitagliptin plasma concentration. The sensitivity of the assay to detect modest increases in QTc interval was established with the active control moxifloxacin. In conclusion, at clinically relevant concentrations, sitagliptin is not associated with clinically meaningful QTcf prolongation.

Beneficial Impact of Xuezhikang on Cardiovascular Events and Mortality in Elderly Hypertensive Patients With Previous Myocardial Infarction From the China Coronary Secondary Prevention Study (CCSPS)

Tue, 14 Jul 2009 18:01:54 PDT

Coronary heart disease, hypertension, and dyslipidemia are highly prevalent and commonly coexist in people who are middle-aged and older. Previous data suggested that lowering cholesterol concentrations in individuals at high risk of cardiovascular disease improved clinical outcomes. Xuezhikang, a partial extract of red yeast rice con taining statin, has a marked impact on lipids. The purpose of this study, therefore, was to evaluate the impact of Xuezhikang on reducing cardiovascular events and mortality in elderly Chinese hypertensive patients with a history of myocardial infarction (MI) enrolled in the Chinese Coronary Secondary Prevention Study. In this randomized trial, 1530 elderly hypertensive patients (≥65 years old) with previous MI were assigned either to placebo (n = 758) or to Xuezhikang (n = 772) daily for an average of 4.5 years. The primary endpoint was recurrent coronary events; the secondary endpoint was all-cause mortality and other clinical events, including adverse effects. There were 68 cases of coronary events (8.8%) detected in the Xuezhikang group and 108 cases (14.3%) in the placebo group (38.2% risk reduction by Xuezhikang therapy). Death from coronary heart disease (CHD) totaled 49 cases in the Xuezhikang group (6.4%) and 68 cases in the placebo group (9.0%), indicating that Xuezhikang significantly decreased the risk of CHD death by 29.2%. Our study demonstrated that Xuezhikang therapy could effectively and safely reduce cardiovascular events and all-cause death in Chinese elderly hypertensive patients with previous MI. This finding may have an important implication for the treatment of elderly hypertensive patients with CHD.

Pharmacological Aspects and Potential New Clinical Applications of Ketamine: Reevaluation of an Old Drug

Aroni, F., Iacovidou, N., Dontas, I., Pourzitaki, C., Xanthos, T. — Tue, 14 Jul 2009 18:01:54 PDT

Ketamine, the phencyclidine derivative described in 1965, is an intravenous anesthetic with a variety of applications. The enthusiasm following its initial release subsided due to side effects from the central nervous system. New anesthetics limited the role of ketamine in anesthetic practice. However, its hemodynamically stable profile, along with its beneficial respiratory properties and analgesic potency, rendered the drug invaluable in battlefield medicine, sedation of the uncooperative child, analgesia, and sedation in burn units. Reevaluation, though, of analgesic properties of ketamine resulted in new interest regarding its use in perioperative and chronic pain management. Moreover, recent studies in the effects of the substance on intracranial pressure and cerebral blood flow led to revising the recommendation against its use in brain injury. Furthermore, the bronchodilating effects of the substance led to increasing interest for potential use in asthma treatment. In addition, separation of the 2 enantiomers and subsequent separate studies indicated beneficial results of the S(+) one. Thus, new controlled multicentered clinical trials are to be conducted to justify approval for new uses of ketamine and take advantage of its unique range of applications.

Influence of Glomerular Filtration Rate on the Pharmacokinetics of Cyclophosphamide Enantiomers in Patients With Lupus Nephritis

Tue, 14 Jul 2009 18:01:54 PDT

The pharmacokinetics of cyclophosphamide (CYC) enantiomers were evaluated in patients with lupus nephritis distributed in 2 groups according to creatinine clearance: group 1 (90.6-144.6 mL/min/1.73 m²) and group 2 (42.8-76.4 mL/min/1.73 m²). All patients were treated with 0.75 to 1.3 g of racemic CYC as a 2-hour infusion and with 1 mg intravenous midazolam as a drug-metabolizing marker. CYC enantiomers and midazolam concentrations in plasma were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The following differences (Wilcoxon test, P ≤ .05) were observed between the (S)-(-) and (R)-(+) enantiomers: AUC_0- 152.41 vs 129.25 µg·h/mL, CL 3.28 vs 3.89 L/h, Vd 31.38 vs 29.74 L, and t_1/2 6.79 vs 5.56 h for group 1 and AUC_0- 167.20 vs 139.08 µg·h/mL, CL 2.99 vs 3.59 L/h, and t_1/2 6.15 vs 4.99 h for group 2. No differences (Mann test, P ≤ .05) were observed between groups 1 and 2 in the pharmacokinetic parameters of both enantiomers. No significant relationship was observed between midazolam clearance (2.92-16.40 mL/min·kg) and clearance of each CYC enantiomer. In conclusion, CYC kinetic disposition is enantioselective, resulting in higher exposures of the (S)-(-) enantiomer in lupus nephritis patients, and the pharmacokinetic parameters of both enantiomers are not altered by the worsening of renal condition.

Prediction of Prasugrel Active Metabolite Concentrations From 2 Downstream Inactive Metabolite Concentrations Using Multilinear Regression Analysis

Ernest, C. S., Heathman, M. A., Wrishko, R. E. — Tue, 14 Jul 2009 18:01:54 PDT

Prasugrel is a thienopyridine prodrug that is metabolized to an active metabolite (Pras-AM), which inhibits adenosine diphosphate (ADP)-induced platelet aggregation. The study objective was to describe a multilinear regression correlation model that was used to quantitatively predict concentrations of Pras-AM from downstream inactive metabolites, R-119251 and R-106583, for the purpose of estimating Pras-AM exposure in patients in the TRITON-TIMI 38 substudies. The model development included 1462 Pras-AM, 1345 R-119251, and 1456 R-106583 concentration data points from 103 healthy participants with a prasugrel dose range of 15 to 80 mg. The model was shown to provide good correlation between predicted and observed concentrations with only a minor deviation of ~6% from the unity line and described the variability within ~4.5%. Examination of the data indicated that regardless of ethnicity, age, weight, moderate hepatic impairment, or renal impairment, predictions were reliable. Predicted Pras-AM concentrations in TRITON-TIMI 38 were comparable with historical data.

Population Pharmacokinetic Analyses to Evaluate the Influence of Intrinsic and Extrinsic Factors on Exposure of Prasugrel Active Metabolite in TRITON-TIMI 38

Tue, 14 Jul 2009 18:01:54 PDT

Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON-TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrel's active metabolite (Pras-AM) concentrations from its 2 downstream inactive metabolites. Population-based methods were then applied to Pras-AM concentration data to characterize the PK. The potential influence of body weight, body mass index, age, sex, renal function, diabetes, tobacco use, and other disease status on Bayesian estimates of Pras-AM exposures was assessed. The PK of Pras-AM was adequately described by a multicompartmental model and consistent with results from previous studies. The systemic exposure of prasugrel was not appreciably affected by body mass index, gender, diabetes, smoking, and renal impairment. Pras-AM mean exposure in patients weighing <60 kg (4.1%) was 30% (90% confidence interval [CI] 1.16-1.45) higher than exposure in patients ≥60 kg. Mean Pras-AM exposures for patients ≥75 years (10.5%) were 19% (90% CI: 1.11-1.28) higher compared with patients <75 years.