The Journal of Clinical Pharmacology current issue

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.