Jace Nielsen

Population Pharmacokinetics of Pegaptanib in Patients With Neovascular, Age-Related Macular Degeneration

The anti—vascular endothelial growth factor (VEGF) aptamer pegaptanib is eliminated primarily by renal clearance. Because renal function declines with age, pegaptanib exposure in patients with age‐related macular degeneration (AMD) may increase. Therefore, a population pharmacokinetic (PK) analysis of pegaptanib was undertaken in Western and Asian AMD patients to determine the influence of renal function on apparent pegaptanib clearance (CL). Pegaptanib (0.3–3 mg per eye) was administered every 4 to 6 weeks to 262 AMD patients in 4 studies. Pegaptanib exposures (area under the concentration—time curve [AUC] and maximum plasma concentration) after 8 doses were similar to exposures following the first dose, consistent with the absence of plasma accumulation. A 1‐compartment model parameterized in terms of the absorption rate constant, apparent volume of distribution, and CL was used to describe the pegaptanib plasma concentration data. Creatinine clearance (CLCR), body weight (WT), and age influenced pegaptanib PK. Decreasing CLCR from 70 to 30 mL/min doubled AUC. After adjustment for CLCR, WT, and age, the model predicted no race differences in CL or AUC. Given that the therapeutic 0.3 mg per eye dose of pegaptanib results in exposures one‐tenth of those observed following the well‐tolerated 3‐mg dose, these results suggest that no dose adjustment is warranted for AMD patients with moderate renal insufficiency (CLCR >30 mL/min).

Influence of Metoprolol Dosage Release Formulation on the Pharmacokinetic Drug Interaction With Paroxetine

Studies have demonstrated an influence of dosage release formulations on drug interactions and enantiomeric plasma concentrations. Metoprolol is a commonly used beta‐adrenergic antagonist metabolized by CYP2D6. The CYP2D6 inhibitor paroxetine has previously been shown to interact with metoprolol tartrate. This open‐label, randomized, 4‐phase crossover study assessed the potential differential effects of paroxetine on stereoselective pharmacokinetics of immediate‐release (IR) tartrate and extended‐release (ER) succinate metoprolol formulations. Ten healthy participants received metoprolol IR (50 mg) and ER (100 mg) with and without paroxetine coadministration. Blood samples were collected over 24 hours for determination of metoprolol plasma enantiomer concentrations. Paroxetine coadministration significantly increased S and R metoprolol area under the plasma concentration‐time curve from time 0 to the 24‐hour blood draw (AUC0‐24h) by 4‐ and 5‐fold, respectively for IR, and 3‐ and 4‐fold, respectively, for ER. S/R AUC ratios significantly decreased. These results demonstrate a pharmacokinetic interaction between paroxetine and both formulations of metoprolol. The interaction is greater with R metoprolol, and stereoselective metabolism is lost. This could theoretically result in greater beta‐blockade and lost cardioselectivity. The magnitude of the interaction was similar between metoprolol formulations, which may be attributable to low doses/drug input rates employed.

The Impact of Paroxetine Coadministration on Stereospecific Carvedilol Pharmacokinetics

Study Objective: To assess the impact of paroxetine coadministration on the stereoselective pharmacokinetic (PK) properties of carvedilol. Design: Prospective, randomized, 2-phase crossover. Setting: The University of Michigan General Clinical Research Unit and Michigan Clinical Research Unit. Participants: Twelve healthy volunteers aged 18 to 45 years, male and female, receiving no treatment with prescription or nonprescription medications. Interventions: Participants received single dose oral carvedilol (12.5 mg) with and without coadministration of immediate-release paroxetine (10 mg orally twice daily), in random order. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, and 24 hours post-carvedilol dose for determination of R and S carvedilol plasma enantiomer concentrations by high pressure liquid chromatography. Measurements and Main Results: Pharmacokinetic (PK) parameters were calculated for each enantiomer by noncompartmental methods and compared between study phases by analysis of variance (ANOVA) controlling for study phase order and subject, with Tukey’s studentized range test post hoc. Area under the concentration-time curve (AUC) increased significantly with paroxetine coadministration, approximately 2.5-fold and 1.9-fold for the R and S enantiomers, respectively. R/S AUC ratio increased significantly, from approximately 2.3 to 3.0. Individual increases in enantiomeric AUCs with paroxetine coadministration ranged from 0% to 571% and changes in R/S ratio ranged from —8% to 108%. Heart rate, P-R interval, and blood pressure were monitored and no clinically significant changes in carvedilol effects were noted. Conclusion. This study demonstrated a PK drug—drug interaction between paroxetine and carvedilol, with considerable interparticipant variability in carvedilol PK parameters and magnitude of drug interaction. Stereoselectivity of carvedilol metabolism is preserved with paroxetine coadministration, and R/S AUC ratio generally widens. Although this drug interaction could potentially increase adrenergic antagonism and have significant clinical effects in patients, these effects were not seen in our healthy volunteer participants.

Longitudinal FEV1 dose-response model for inhaled PF-00610355 and salmeterol in patients with chronic obstructive pulmonary disease.

The objective of this work was to characterize the dose–response relationship between two inhaled long-acting beta agonists (PF-00610355 and salmeterol) and the forced expiratory volume in one second (FEV1) in order to inform dosing recommendations for future clinical trials in patients with chronic obstructive pulmonary disease (COPD). This meta-analysis of four studies included 8,513 FEV1 measurements from 690 patients with moderate COPD. A longitudinal kinetic-pharmacodynamic (K-PD) model was developed and adequately described changes in FEV1 measurements over time, including circadian patterns within a day, as well as changes in FEV1 measurements elicited from administration of PF-00610355 or salmeterol. The fine-particle dose, the amount of drug present in particles small enough for lung delivery, was used as the exposure measure for PF-00610355. Greater reversibility following administration of a short-acting beta agonist during run-in was associated with increased FEV1 response to long-acting beta agonists (through an increased maximal response, Emax). Simulations were conducted to better understand the response to PF-00610355 relative to placebo and salmeterol. The results of the simulations show that once daily fine-particle doses of 28.1xa0μg versus placebo have a moderate probability of providing an average improvement above 100xa0mL at trough. The 50xa0μg fine-particle dose, on the other hand, has a greater than 0.78 probability of achieving a 120xa0mL improvement versus placebo at trough. From an efficacy perspective and assuming a fine-particle fraction of 25xa0% for the Phase 3 formulation; 100 and 200xa0μg once daily nominal doses would be of interest to investigate in future Phase 3 trials.

Population Pharmacokinetics Analysis of Vigabatrin in Adults and Children with Epilepsy and Children with Infantile Spasms

Background and objectivesVigabatrin is an inhibitor of γ-aminobutyric acid transaminase. The purpose of these analyses was to develop a population pharmacokinetics model to characterize the vigabatrin concentration–time profile for adults and children with refractory complex partial seizures (rCPS) and for children with infantile spasms (IS); to identify covariates that affect its disposition, and to enable predictions of systemic vigabatrin exposure for patients 1–12xa0months of age.MethodsVigabatrin pharmacokinetic data from six randomized controlled clinical trials and one open-label study were analyzed using nonlinear mixed-effects modeling. Data collected from 349 adults with rCPS and 119 pediatric patients with rCPS or IS were used in the analyses.ResultsA two-compartment model with first-order elimination and transit-compartment absorption consisting of five transit compartments adequately described the vigabatrin concentration–time data for these adult and pediatric patient populations. An exponential error model was used to estimate inter-individual variability for the transit-rate constant (ktr) (24.2xa0%), elimination rate constant (k) (14.7xa0%) and apparent central volume of distribution (Vc/F) (18xa0%). For the study of children with IS, inter-occasion variability was estimated for ktr (58.1xa0%) and relative bioavailability (F) (26.9xa0%). Covariate analysis indicated that age, creatinine clearance (CLCR), and body weight were important predictors of vigabatrin pharmacokinetic parameters. Vigabatrin apparent clearance increased with increasing CLCR, consistent with renal excretion (primary pathway of vigabatrin elimination). Rate of vigabatrin absorption was dependent on age. The rate was slower in younger patients, which resulted in a smaller predicted maximum concentration and longer predicted time to maximum concentrations. Vigabatrin Vc/F, apparent inter-compartmental clearance between the central and peripheral compartment, and apparent peripheral volume of distribution were increased with greater patient body weights. Sex did not contribute significantly to vigabatrin pharmacokinetic variability.ConclusionThe model adequately described vigabatrin pharmacokinetic and enabled predictions of systemic exposures in pediatric patients 1–12xa0months of age.

Population dose-response analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures.

Vigabatrin is an irreversible inhibitor of γ‐aminobutyric acid transaminase (GABA‐T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might impact seizure frequency. This population dose–response analysis used seizure‐count data from three pediatric and two adult randomized controlled studies of rCPS patients. A negative binomial distribution model adequately described daily seizure data. Mean seizure rate decreased with time after first dose and was described using an asymptotic model. Vigabatrin drug effects were best characterized by a quadratic model using normalized dosage as the exposure metric. Normalized dosage was an estimated parameter that allowed for individualized changes in vigabatrin exposure based on body weight. Baseline seizure rate increased with decreasing age, but age had no impact on vigabatrin drug effects after dosage was normalized for body weight differences. Posterior predictive checks indicated the final model was capable of simulating data consistent with observed daily seizure counts. Total normalized vigabatrin dosages of 1, 3, and 6u2009g/day were predicted to reduce seizure rates 23.2%, 45.6%, and 48.5%, respectively.

Vigabatrin pediatric dosing information for refractory complex partial seizures: Results from a population dose–response analysis

We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose–response model related seizure‐count data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure‐count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1 g/day adult dosage were 350 and 450 mg/day for patients with body weight ranges 10–15 and >15–20 kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3 g/day adult dosage were 1,050 and 1,300 mg/day for weight ranges 10–15 and >15–20 kg, respectively. Predicted tablet dosage for efficacy comparable to a 1 g/day adult dosage was 500 mg/day for weight ranges 25–60 kg. Predicted tablet dosage for efficacy comparable to a 3 g/day adult dosage was 2,000 mg for weight ranges 25–60 kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights ≥10 kg.

Population exposure–response analysis of cabozantinib efficacy and safety endpoints in patients with renal cell carcinoma

BackgroundIn the phase III METEOR trial, tyrosine kinase inhibitor cabozantinib significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival compared to everolimus in patients with advanced renal cell carcinoma (RCC) who had received prior VEGFR inhibitor therapy. In METEOR, RCC patients started at a daily 60-mg cabozantinib tablet (Cabometyx™) dose but could reduce to 40- or 20-mg to achieve a tolerated exposure.Objectives and methodsExposure–response (ER) models were developed to characterize the relationship between cabozantinib at clinically relevant exposures in RCC patients enrolled in METEOR and efficacy (PFS and tumor response) and safety endpoints.ResultsCompared to the average steady-state cabozantinib concentration for a 60-mg dose, exposures at simulated 40- and 20-mg starting doses were predicted to result in higher risk of disease progression or death [hazard ratios (HRs) of 1.10 and 1.39, respectively], lower maximal median reduction in tumor size (−u200911.9 vs −u20099.1 and −u20094.5%, respectively), and lower ORR (19.1 vs 15.6 and 8.7%, respectively). The 60-mg exposure was also associated with higher risk for selected adverse events (AEs) palmar-plantar erythrodysesthesia syndrome (gradeu2009≥u20091), fatigue/asthenia (gradeu2009≥u20093), diarrhea (gradeu2009≥u20093), and hypertension (predicted HRs of 2.21, 2.01, 1.78, and 1.85, respectively) relative to the predicted average steady-state cabozantinib concentration for a 20-mg starting dose.ConclusionER modeling predicted that cabozantinib exposures in RCC patients at the 60-mg starting dose would provide greater anti-tumor activity relative to exposures at simulated 40- and 20-mg starting doses that were associated with decreased rates of clinically relevant AEs.

A population pharmacokinetic model of cabozantinib in healthy volunteers and patients with various cancer types

PurposeAn integrated population pharmacokinetic (popPK) model was developed to describe the pharmacokinetics (PK) of tyrosine kinase inhibitor cabozantinib in healthy volunteers (HVs) and patients with various cancer types and to identify any differences in cabozantinib PK across these populations.MethodsPlasma concentration data used to develop the popPK model were obtained from nine clinical trials (8072 concentrations from 1534 HVs or patients) of cabozantinib in HVs and patients with renal cell carcinoma (RCC), medullary thyroid carcinoma (MTC), glioblastoma multiforme, castration-resistant prostate cancer, or other advanced malignancies.ResultsPK data across studies were adequately characterized by a two-compartment disposition model with dual first- and zero-order absorption processes and first-order elimination. Baseline demographic covariates (age, weight, gender, race, and cancer type) were generally predicted to have a small-to-moderate impact on apparent clearance (CL/F). However, MTC cancer type did show an approximately 93% higher CL/F relative to HVs following chronic dosing, resulting in approximately 40–50% lower predicted steady-state cabozantinib plasma concentrations.ConclusionThis popPK analysis showed cabozantinib CL/F values to be higher for patients with MTC and may account for the higher dosage required in this patient population (140-mg) to achieve plasma exposures comparable to those in patients with RCC and other tumor types administered a 60-mg cabozantinib tablet dose. Possible factors that may underlie the higher cabozantinib clearance observed in MTC patients are discussed.

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized by a two‐compartment PPK model with first‐order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P‐glycoprotein (P‐gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P‐gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose‐reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5‐mg and 5‐mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.