Megan A. Gibbs

Single-Dose Pharmacokinetics of Varenicline, a Selective Nicotinic Receptor Partial Agonist, in Healthy Smokers and Nonsmokers

Varenicline is a novel and selective α4β2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double‐blind, placebo‐controlled, single‐dose, dose‐escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time‐of‐day dosing did not affect the pharmacokinetics of varenicline.

Multiple‐Dose Pharmacokinetics of the Selective Nicotinic Receptor Partial Agonist, Varenicline, in Healthy Smokers

Varenicline is a novel and selective α4β2 nicotinic acetylcholine receptor partial agonist developed for smoking cessation. The primary objectives of this double‐blind, placebo‐controlled, dose‐escalation study were to determine the pharmacokinetics, safety, and tolerability of multiple oral doses of varenicline given as tablets once (1 mg, 2 mg, and 3 mg) or twice (1 mg) daily to healthy adult smokers. Within each dose level, 8 subjects were randomized to varenicline and 4 subjects to placebo. Varenicline was well tolerated at doses up to and including 2 mg daily. Dose‐proportional increases in maximum observed plasma concentrations and area under the plasma concentration‐time curve from time zero to the end of the dosing interval values were observed between the 1‐mg and 2‐mg daily doses of varenicline. Once‐ and twice‐daily dosing resulted, on average, in an approximate 2‐ and 3‐fold increase in varenicline systemic exposure, respectively, compared with single dose. There was no evidence of concentration‐ or time‐dependent changes in the pharmacokinetics of varenicline upon repeat dosing.

Factors affecting the clinical development of cytochrome p450 3A substrates.

The objective of this review is to evaluate the risks associated with the discovery and development of cytochrome P450 (CYP) 3A substrates.CYP3A is the most abundant P450 enzyme in human liver and is highly expressed in the intestinal tract. The enzyme contributes substantially to metabolism of approximately 50% of currently marketed drugs that undergo oxidative metabolism. As a result, drug-drug interactions involving inhibitors of CYP3A-mediated metabolism can be of great clinical consequence.It is the position of the authors that, because of the factors responsible for the broad substrate specificity of CYP3A, discovery and development of compounds across a large and broad portfolio that are completely devoid of CYP3A metabolism is not feasible. Thus, it is important that scientifically valid approaches to the discovery and development of compounds metabolised by CYP3A be realised. The clinical relevance of CYP3A metabolism is dependent on a multitude of factors that include the degree of intestinal and hepatic CYP3A-mediated first-pass extraction, the therapeutic index of the compound and the adverse event associated with inhibition of CYP3A metabolism. Thus, a better understanding of the disposition of a CYP3A-metabolised compound relative to the projected or observed therapeutic index (or safety margin) can provide ample evidence to support the continued development of a CYP3A substrate.This document will highlight current practices as well as the benefits and risks associated with those practices.

Central Nervous System Pharmacokinetics of the Mdr1 P-Glycoprotein Substrate CP-615,003: Intersite Differences and Implications for Human Receptor Occupancy Projections from Cerebrospinal Fluid Exposures

The central nervous system (CNS) distribution and transport mechanisms of the investigational drug candidate CP-615,003 (N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide) and its active metabolite CP-900,725 have been characterized. Brain distribution of CP-615,003 and CP-900,725 was low in rats and mice (brain-to-serum ratio < 0.2). Cerebrospinal fluid (CSF)-to-serum ratios of CP-615,003 were 6- to 8-fold lower than the plasma unbound fraction in rats and dogs. In vitro, CP-615,003 displayed quinidine-like efflux in MDR1-expressing Madin-Darby canine kidney II cells. The brain-to-serum ratio of CP-615,003 in mdr1a/1b (–/–) mice was ∼7 times that in their wild-type counterparts, confirming that impaired CNS distribution was explained by P-gp efflux transport. In contrast, P-gp efflux did not explain the impaired CNS penetration of CP-900,725. Intracerebral microdialysis was used to characterize rat brain extracellular fluid (ECF) distribution. Interestingly, the ECF-to-serum ratio of the P-gp substrate CP-615,003 was 7-fold below the CSF-to-serum ratio, whereas this disequilibrium was not observed for CP-900,725. In a clinical study, steady-state CSF exposures were measured after administration of 100 mg of CP-615,003 b.i.d. The human CSF-to-plasma ratios of CP-615,003 and CP-900,725 were both ∼10-fold below their ex vivo plasma unbound fractions, confirming impaired human CNS penetration. Preliminary estimates of CNS receptor occupancy from human CSF concentrations were sensitive to assumptions regarding the magnitude of the CSF-ECF gradient for CP-615,003 in humans. In summary, this case provides an example of intersite differences in CNS pharmacokinetics of a P-gp substrate and potential implications for projection of human CNS receptor occupancy of transporter substrates from CSF pharmacokinetic data when direct imaging-based approaches are not feasible.

Quantitative Model of the Relationship Between Dipeptidyl Peptidase‐4 (DPP‐4) Inhibition and Response: Meta‐Analysis of Alogliptin, Saxagliptin, Sitagliptin, and Vildagliptin Efficacy Results

Dipeptidyl peptidase‐4 (DPP‐4) inhibition is a well‐characterized treatment for type 2 diabetes mellitus (T2DM). The objective of this model‐based meta‐analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). Publicly available data involving late‐stage or marketed DPP‐4 inhibitors were leveraged for the analysis. Nonlinear mixed‐effects modeling was performed to describe the relationship between DPP‐4 inhibition and mean response over time. Plots of the relationship between metrics of DPP‐4 inhibition (ie, weighted average inhibition [WAI], time above 80% inhibition, and trough inhibition) and response after 12 weeks of daily dosing were evaluated. The WAI was most closely related to outcome, although other metrics performed well. A model was constructed that included fixed effects for placebo and drug and random effects for intertrial variability and residual error. The relationship between WAI and outcome was nonlinear, with an increasing response up to 98% WAI. Response to DPP‐4 inhibitors could be described with a single drug effect. The WAI appears to be a useful index of DPP‐4 inhibition related to HbA1c. Biomarker to response relationships informed by model‐based meta‐analysis can be leveraged to support study designs including optimization of dose, duration of therapy, and patient population.

Displacement of Serotonin and Dopamine Transporters by Venlafaxine Extended Release Capsule at Steady State: A [123I]2??-Carbomethoxy-3??-(4-Iodophenyl)-Tropane Single Photon Emission Computed Tomography Imaging Study

Both positron emission tomography and single photon emission computed tomography (SPECT) studies suggest that saturation of serotonin transporters (SERT) is present during treatment with therapeutic doses of selective serotonin reuptake inhibitors (SSRIs). Selective serotonin reuptake inhibitors also appear to increase the availability of dopamine transporters (DAT). The current study measured SERT occupancy and modulation of DAT by the serotonin/norepinephrine reuptake inhibitor (SNRI) venlafaxine using [123I]2β-carbomethoxy-3β-(4-iodophenyl)-tropane SPECT. Eight healthy subjects were administered open-label venlafaxine extended release capsules (75 mg/d for 4 days followed by 150 mg/d for 5 days). Venlafaxine significantly inhibited [123I]β-CIT binding to SERT in the brainstem (55.4%) and the diencephalon (54.1%). In contrast, venlafaxine increased [123I]β-CIT binding to DAT in the striatum (10.1%) after 5 days of administration of 150 mg/d. The displacement of [123I]β-CIT from brain SERT and the increase in striatal [123I]β-CIT binding to DAT appear similar to previous work with the SSRI citalopram (40 mg/d). A literature review of SERT occupancy by marketed SSRIs and the SNRI venlafaxine using SPECT ([123I]β-CIT) or positron emission tomography ([11C](N, N-Dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine) imaging suggests that therapeutic doses of SNRI are associated with virtual saturation of the serotonin transporter.

Evaluation of structural models to describe the effect of placebo upon the time course of major depressive disorder

Major depressive disorder (MDD) is the leading cause of disability in many countries. Designing and evaluating clinical trials of antidepressants is difficult due to the pronounced and variable placebo response which is poorly defined and may be affected by trial design. Approximately half of recent clinical trials of commonly used antidepressants failed to show statistical superiority for the drug over placebo, which is partly attributable to a marked placebo response. These failures suggest the need for new tools to evaluate placebo response and drug effect in depression, as well as to help design more informative clinical trials. Disease progression modeling is a tool that has been employed for such evaluations and several models have been proposed to describe MDD. Placebo data from three clinical depression trials were used to evaluate three published models: the inverse Bateman (IBM), indirect response (IDR) and transit (TM) models. Each model was used to describe Hamilton Rating Scale for major depression (HAMD) data and results were evaluated. The IBM model had several deficiencies, making it unsuitable. The IDR and TM models performed well on most evaluations and appear suitable. Comparing the IDR and TM models showed less clear distinctions, although overall the TM was found to be somewhat better than the IDR model. Model based evaluation can provide a useful tool for evaluating the time course of MDD and detecting drug effect. However, the models used should be robust, with well estimated parameters.

A model-based meta-analysis of monoclonal antibody pharmacokinetics to guide optimal first-in-human study design.

The objectives of this retrospective analysis were (1) to characterize the population pharmacokinetics (popPK) of four different monoclonal antibodies (mAbs) in a combined analysis of individual data collected during first-in-human (FIH) studies and (2) to provide a scientific rationale for prospective design of FIH studies with mAbs. The data set was composed of 171 subjects contributing a total of 2716 mAb serum concentrations, following intravenous (IV) and subcutaneous (SC) doses. mAb PK was described by an open 2-compartment model with first-order elimination from the central compartment and a depot compartment with first-order absorption. Parameter values obtained from the popPK model were further used to generate optimal sampling times for a single dose study. A robust fit to the combined data from four mAbs was obtained using the 2-compartment model. Population parameter estimates for systemic clearance and central volume of distribution were 0.20 L/day and 3.6 L with intersubject variability of 31% and 34%, respectively. The random residual error was 14%. Differences (> 2-fold) in PK parameters were not apparent across mAbs. Rich designs (22 samples/subject), minimal designs for popPK (5 samples/subject), and optimal designs for non-compartmental analysis (NCA) and popPK (10 samples/subject) were examined by stochastic simulation and estimation. Single-dose PK studies for linear mAbs executed using the optimal designs are expected to yield high-quality model estimates, and accurate capture of NCA estimations. This model-based meta-analysis has determined typical popPK values for four mAbs with linear elimination and enabled prospective optimization of FIH study designs, potentially improving the efficiency of FIH studies for this class of therapeutics.

Applications of Computer-Aided Pharmacokinetic and Pharmacodynamic Methods from Drug Discovery Through Registration

Computer-aided pharmacokinetic, pharmacodynamic, and pharmacokinetic/pharmacodynamic methods are commonly applied to quantify the disposition and the pharmacological effects of the drug, to explore exposure-response relationships, and to predict safety and efficacy outcomes. Use of modeling and simulation throughout the drug development continuum can support more efficient preclinical and clinical study design and interpretation. Mechanism-based approaches where sound biological understanding exists provide meaningful quantitative comparisons between candidates and are sought to support science-based decisions. Simulations from these models allow for scientists to investigate a variety of trial designs where assumptions are clearly stated. The objectives of this review article are to describe commercially available PK/PD software packages and present examples of their application in drug discovery and development. With industry and regulatory support, use of exposure response information may optimize the path to delivery of new medicines to patients. This review is focused on the most common computer software applications in discovery through early development (i.e., GastroPlus, Simcyp Population-based ADME simulator, SAAM II, and WinNonlin), in development (i.e., NONMEM, ADAPT II, MATLAB, WinBUGS, Trial Simulator, and Drug Model Explorer), and across the continuum for data management (i.e., SAS, S-PLUS, and R).

Absolute Oral Bioavailability of Traxoprodil in Cytochrome P450 2D6 Extensive and Poor Metabolisers

BackgroundTraxoprodil, a substituted 4-phenylpiperidine, is an N-methyl-D-aspartate (NMDA) receptor antagonist that is selective for receptors containing the NR2B subunit. In vivo and in vitro studies examining the disposition of traxoprodil have demonstrated that it is mainly metabolised by cytochrome P450 (CYP) 2D6, a major drug-metabolising enzyme that exhibits a genetic polymorphism.ObjectiveTo assess the single-dose absolute oral bioavailability of traxoprodil in healthy male volunteers phenotyped as either CYP2D6 extensive or poor metabolisers.MethodsThis was an open-label, three-way crossover study. Traxoprodil was administered as a single dose orally in solution of 50, 100 and 300mg and intravenously as a constant rate 2-hour infusion of 50 and 100mg. CYP2D6 phenotype was assigned following single-dose dextromethorphan administration.ResultsIn poor metabolisers (n = 6), oral bioavailability was ∼80% and was consistent with a liver extraction ratio of ∼20% (plasma clearance of ∼4 mL/min/ kg) indicating near complete absorption. Following intravenous administration, the mean volume of distribution at steady state (Vss) was moderate (∼6.5 L/kg) and the mean elimination half-life (t1/2) was ∼20 hours. Following oral administration the mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) increased approximately proportionally with dose. In extensive metabolisers (n = 11), oral bioavailability was dose-dependent and nonlinear. At the 100mg dose, the absolute oral bioavailability was ∼39.5%. Overall, the oral bioavailability ranged from 22.8% to 62.1% and its estimation was confounded by large differences in plasma concentrations at oral doses without equivalent intravenous doses. Following intravenous administration, plasma clearance was high (∼27 mL/min/kg), the Vss was moderate (∼4 L/Kg) and the t1/2 was ∼2–4 hours. Following oral administration the Cmax and AUC∞ increased more than proportionally with dose. Apparent oral clearance decreased with increasing oral dose. However, t1/2 was approximately the same at all doses (∼4 hours).ConclusionThe pharmacokinetics of traxoprodil were quite different in the two phenotypes. In extensive metabolisers, the oral bioavailability was nonlinear and dose-dependent, while in poor metabolisers, oral bioavailability appeared to be linear and dose-independent. Based on the pharmacokinetics in extensive and poor metabolisers, the nonlinear oral bioavailability in extensive metabolisers may be attributed to saturation of hepatic first-pass CYP2D6 metabolism. Thus, at a high oral dose, the impact of CYP2D6 metabolism on traxoprodil pharmacokinetics is minimal.