Bela Rajiv Patel

Pharmacokinetic and Pharmacodynamic Basis for Effective Argatroban Dosing in Pediatrics

The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of argatroban in pediatric patients and derive dosing recommendations. An open‐label multicenter trial was conducted in pediatric patients (n = 18 from birth to 16 years). A population modeling approach was used to characterize pharmacokinetics and pharmacodynamics of argatroban in pediatric patients. Simulations were performed to derive a dosing regimen for pediatric patients. The estimated clearance of argatroban in pediatric patients was 2‐fold lower than that in healthy adults. Body weight was significant predictor of argatroban clearance. The clearance in a typical 20‐kg pediatric patient was 3.1 L/h. In 4 patients with elevated serum bilirubin levels, the estimated clearance was 0.6 L/h. Effect on activated plasma thromboplastin time (aPTT) was found to be concentration dependent. Simulations suggested that a starting dose of 0.75 μg/kg/min in pediatric patients was comparable in performance to 2.0 μg/kg/min approved in adults for attaining target aPTT and risk for bleeding. A dose increment step size of 0.25 μg/kg/min was suitable for titration. The PK/PD of argatroban was reasonably characterized in pediatrics. Plasma concentration—aPTT relationship was used to derive a safe starting dose and titration scheme for the first time in pediatric patients and was incorporated into the US prescribing information for argatroban.

Population pharmacokinetics of ofatumumab in patients with chronic lymphocytic leukemia, follicular lymphoma, and rheumatoid arthritis

Ofatumumab is a human monoclonal antibody directed at CD20 approved for treatment of chronic lymphocytic leukemia. The population pharmacokinetics of intravenous ofatumumab were characterized in patients with relapsed/refractory chronic lymphocytic leukemia, relapsed/refractory follicular lymphoma, and rheumatoid arthritis, diseases with widely varying CD20+ B‐cell counts in blood. Serum concentration data from a total of 477 patients who received ofatumumab doses ranging from 100 mg to 2000 mg in different dosing regimens were analyzed to determine the pharmacokinetic characteristics of ofatumumab across different patient groups and to identify factors contributing to the pharmacokinetic variability. Ofatumumab pharmacokinetics were well described by a linear two‐compartment model component to represent non‐specific monoclonal antibody clearance from the central compartment interacting with a model component representing the target‐mediated clearance of ofatumumab by binding to CD20 expressed on B cells. The clearance (7.5 mL/h) and steady‐state volume of distribution (5.3 L) for the linear, non‐specific component were consistent with results obtained for other monoclonal antibodies. The target‐mediated clearance component was related to the disease‐specific number of circulating B cells, which will allow simulation of the contribution of target‐mediated clearance to ofatumumab pharmacokinetics in untested disease states with data on B‐cell counts and turnover.

Tafenoquine at therapeutic concentrations does not prolong fridericia-corrected QT interval in healthy subjects

Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single‐blind, randomized, placebo‐ and active‐controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18–65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre‐defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post‐final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine–QTcF concentration–effect relationship demonstrated a shallow slope (0.5 ms/μg mL–1) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization.

Extended acclimatization is required to eliminate stress effects of periodic blood-sampling procedures on vasoactive hormones and blood volume in beagle dogs.

Important in all experimental animal studies is the need to control stress stimuli associated with environmental change and experimental procedures. As the stress response involves alterations in levels of vasoactive hormones, ensuing changes in cardiovascular parameters may confound experimental outcomes. Accordingly, we evaluated the duration required for dogs (n = 4) to acclimatize to frequent blood sampling that involved different procedures. On each sampling occasion during a 6-week period, dogs were removed from their pen to a laboratory area and blood was collected either by venepuncture (days 2, 15, 34, 41) for plasma renin activity (PRA), epinephrine (EPI), norepinephrine, aldosterone, insulin, and atrial natriuretic peptide, or by cannulation (dogs restrained in slings; days 1, 8, 14, 22, 30, 33, 37, 40) for determination of haematocrit (HCT) alone (days 1 to 22) or HCT with plasma volume (PV; days 30 to 40). PRA was higher on days 2 and 15 compared with days 34 and 41 and had decreased by up to 48% by the end of the study (day 41 vs day 15; mean/SEM: 1.18/0.27 vs 2.88/0.79 ng ANG I/ml/h, respectively). EPI showed a time-related decrease from days 2 to 34, during which mean values had decreased by 51% (mean/SEM: 279/29 vs 134/20.9 pg/ml for days 2 and 34, respectively), but appeared stable from then on. None of the other hormones showed any significant variability throughout the course of the study. HCT was relatively variable between days 1 to 22 but stabilized from day 30, after which all mean values were approximately 6% lower than those between days 1 and 8. We conclude that an acclimatization period of at least 4 weeks is required to eliminate stress-related effects in dogs associated with periodic blood sampling.

Utility of concentration‐effect modeling and simulation in a thorough QT study of losmapimod

A thorough QT study was conducted in healthy volunteers with losmapimod. Four treatment regimens were included: a therapeutic dose (7.5 mg BID for 5 days), a supratherapeutic dose (20 mg QD for 5 days), a positive control (400 mg moxifloxacin single dose on Day 5), and placebo for 5 days. Baseline and on treatment ECGs were measured on Day 1 (3 timepoints predose) and Day 5, respectively. The primary statistical analysis failed to demonstrate a lack of effect of losmapimod on the QT interval leading to a positive finding. However, simulations using the concentration‐effect model established for QTcF vs. losmapimod concentration at concentrations 4× the maximum concentration of the therapeutic dose did not exceed the regulatory thresholds of concern of 5 milliseconds for the mean (4.57 milliseconds) and 10 milliseconds for the upper bound of the 90%CI (90%CI 2.88, 6.10). Modeling demonstrated that the discrepant results may have been due to a baseline shift after repeat dosing and baseline differences between the treatments. Considering the results of the concentration‐effect modeling, previous losmapimod data, and the high false‐positive rate associated with the ICH E14 statistical analysis, the statistical analysis was likely a false‐positive.

Validation of MRI Measurement of Cardiac Output in the Dog: The Effects of Dobutamine and Minoxidil

The use of magnetic resonance imaging (MRI) for the measurement of cardiac output parameters in anesthetized adult male beagle dogs has been validated against a widely accepted thermodilution method. Using a multislice cine gradient echo MRI method to acquire images of the entire heart, left ventricular lumen volumes were measured at systole and diastole in seven animals. Cardiac output correlated well (R 2 = 0.88) with thermodilution measurements made in a parallel manner, both before and during acute stimulation with the inotrope dobutamine. In a chronic study of changes in cardiac morphology and function brought about by the antihypertensive minoxidil, MRI reliably detected the expected increases in stroke volume (28%) and cardiac output (58%) resulting from neural reaction to decreased blood pressure. Left ventricular lumen enlarged as well in response to fluid retention and plasma volume increase. Two in four minoxidil-treated animals also developed clear MRI-visible pericardial effusion.

A definitive study of the effects of PDE-5 inhibitors on cardiac repolarization in middle-age males

Patients with erectile dysfunction may use PDE5 inhibitors such as vardenafil (V) and sildenafil (S), which alter the hERG channel of transfected cells only at suprapharmacologic nonclinical concentrations. This study evaluated effects of therapeutic and supratherapeutic doses of V and S on QT/QTc duration. A placebo‐ and active‐control (moxifloxacin, M, at therapeutic dose), period balanced, double blinded, 6 way crossover study evaluated single oral doses of V 10 mg, V 80 mg, S 50 mg, S 400 mg, M 400 mg and placebo in 58 healthy men (mean age 53) with doses separated by 3 days. Six replicate 12‐lead digital ECGs were recorded at 3 time points prior to and 5 time points post dose to cover the full exposure of drugs and metabolites. An independent lab blindly analyzed the ECGs. PK blood samples were drawn at the same 5 time points post dose. For placebo, mean change in QTcF (Fridericia) duration from baseline at 1 hour post dose (approximate Tmax of V and S) was 0 msec (+/‐ 0.7 SD). QT and QTc variability was small across regimens, indicating statistically powerful results due to large sample size and number (17,000) of ECGs. M demonstrated an expected 8 msec mean change and was the only drug to prolong absolute QT. Placebo‐corrected values of mean change from baseline at 1 hour post‐dose for each regimen are shown below. QT corrected using linear and nonlinear methods and each individuals QT/HR data (QTci) yielded similar trends of drug effect on QTc. PK/PD modeling demonstrated a very shallow QTc‐concentration relationship for V and S. Therapeutic and supratherapeutic doses of V and S produced no increase of absolute QT and similar small increases in QTc interval. We conclude that these findings, and the absence of postmarketing reports of torsades de pointes with S, indicate that small increases in QTc for V and S are clinically insignificant. This study design may serve as a guide for future definitive QT assessment. (See Table )

Reporting guidelines for population pharmacokinetic analyses

The purpose of this work was to develop a consolidated set of guiding principles for reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (where population PK frequently serves as preparatory analysis to exposure–response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two main purposes of population PK reports (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified two main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results, and (2) a scientifically literate, but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with six questions that need to be addressed throughout the report. We recommend eight sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including PKPD and simulation reports.

Population pharmacokinetics modeling and analysis of foretinib in adult patients with advanced solid tumors

Foretinib is a multikinase inhibitor that inhibits multiple receptor tyrosine kinases, including MET and VEGFR, with the potential for treatment of solid tumors. Hepatocellular carcinoma (HCC) pathogenesis is associated with overexpression of MET, and physiologic changes in the livers of HCC patients may decrease CYP3A isozyme‐mediated metabolism of foretinib. A population pharmacokinetic model of foretinib was developed to explore the effect of tumor type, formulation, and other covariates. Data from 1 HCC study in Asia and 3 non‐HCC studies in the United States with varying foretinib regimens and formulations were used for analysis. A 2‐compartment model with a linear first‐order absorption and elimination and lag time in absorption adequately described foretinib pharmacokinetics in 132 advanced non‐HCC and HCC patients and identified an effect of formulations on bioavailability. The bisphosphate salt capsules and freebase tablets had a relative bioavailability 37% and 20% higher, respectively, than the solution formulation. HCC patients had ≈19.6% lower mean clearance (70.14 L/h), ≈16% lower mean volume of distribution (1725.6 L), and higher dose‐normalized exposure compared with non‐HCC patients. This could be a result of differences in metabolism in HCC patients, body weight, or activity of CYP3A isozymes between Asian and Western cancer patients.

PK/PD modeling of QTC duration for vardenafil & sildenafil in healthy volunteers

A placebo‐ and positive‐controlled (Moxifloxacin, M 400 mg), double‐blind, 6‐way crossover study evaluated the effects of single oral therapeutic and supratherapeutic doses of vardenafil (V 10, 80 mg), and sildenafil (S 50, 400 mg) on QT/QTcF duration.