Dosing Recommendation Based on the Effects of Different Meal Types on Pexidartinib Pharmacokinetics in Healthy Subjects: Implementation of Model-informed Drug Development Strategy.

Pexidartinib, an oral small molecule inhibitor of the colony-stimulating factor 1 receptor, is approved for treatment of adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The original dosing regimen is 400 mg of pexidartinib (2 × 200-mg capsules) twice daily, administered on an empty stomach at least 1 hour before or 2 hours after a meal or snack. Because pexidartinib is likely to be taken over an extended period of time, the ability to take pexidartinib with a meal would simplify timing of administration and potentially improve compliance. Since administering 400 mg of pexidartinib with a low-fat meal increases exposure by ≈60% relative to the fasted state, administering 250 mg of pexidartinib with a low-fat meal (low-fat meal dosing regimen) was predicted to achieve an exposure similar to 400 mg administered during a fasted state (original dosing regimen). Based on clinical trial simulations with two one-sided t-tests and bootstrapping (ie, resampling) analyses, a bioequivalence study (n = 24) would have >90% power to conclude that the original dosing regimen (400 mg fasted twice daily) and the low-fat meal dosing regimen (250 mg with a low-fat meal twice daily) are bioequivalent. This report provides the outcome of the implementation of the model-informed drug development strategy to recommend and justify a low-fat meal dosing regimen for pexidartinib that has the potential to improve patient compliance while maintaining drug exposure.

Physiologically-based pharmacokinetic modeling of immunoglobulin and antibody coadministration in patients with primary human immunodeficiency.

Intravenous immunoglobulin (IVIG) (2000 mg/kg) increased the clearance of the mouse monoclonal antibody 7E3, directed against platelet integrin IIb/IIIa (alpha IIb beta 3, CD41/CD61) in rodents. We wanted to investigate the effect of IVIG on clearance of monoclonal antibodies in humans as there is extremely limited data regarding this interaction in the literature. Using the tyrosine protein kinase KIT anti-cluster of differentiation 117 (c-Kit) humanized monoclonal antibody (JSP191) as a case study, we used physiologically-based pharmacokinetic (PBPK) modeling to evaluate the pharmacokinetic interaction between monoclonal antibodies and IVIG at doses (300-600 mg/kg) administered to patients with primary human immunodeficiency (PI). We first characterized the interaction between monoclonal antibodies and IVIG in PK-Sim®/MoBi® using published literature data, including the following: IVIG plus 7E3 in mice and rats and IVIG plus the human anti-C5 monoclonal antibody tesidolumab in adults with end-stage renal disease. We next developed a PBPK model using digitized data for JSPI91 alone in older adults with myelodysplastic syndrome and acute myeloid leukemia and in pediatric patients with severe combined immunodeficiency (SCID). Finally, we simulated the impact of IVIG (300-2000 mg/kg) coadministration with JSP191 on the area under the curve of JSP191 in patients with SCID. Model predictions were within 1.5-fold of observed values for 7E3 plus IVIG and tesidolumab plus IVIG as well as for JSP191 administered alone. Based on our simulations, IVIG doses ≥500 mg exceeded the 80%-125% no-effect boundaries. IVIG treatment with monoclonal antibodies in patients with PI may result in a clinically significant interaction depending on the IVIG dose administered and the exposure-response relationship for the specific monoclonal antibody.

Edoxaban Exposure in Patients With Atrial Fibrillation and Estimated Creatinine Clearance Exceeding 100 mL/min.

Edoxaban 60 mg is approved for stroke prevention in patients with atrial fibrillation (AF) not fulfilling any dose-reduction criteria. As edoxaban is partially renally cleared (≈50%), this study compared pharmacokinetics (PK) and pharmacodynamics of edoxaban 60 mg once daily with edoxaban 75 mg once daily in patients with AF with high renal clearance (creatinine clearance > 100 mL/min) over 12 months. Primary PK and pharmacodynamics end points were plasma edoxaban exposure and anti-factor Xa (FXa) concentration. A population PK model estimated edoxaban exposure at steady state. Efficacy and safety outcomes included composites of stroke, transient ischemic attack, systemic embolism, and major and clinically relevant nonmajor bleeding. Of 607 patients, 303 and 304 were randomized to edoxaban 60 and 75 mg, respectively. Edoxaban 75 mg provided ≈25% higher exposure than 60 mg. This increase was accurately depicted in the population PK model; anti-factor Xa concentration correlated with edoxaban exposure. Rates of composite and individual outcomes were similarly low between doses. In conclusion, the 25% increase in edoxaban dose (60-75 mg) resulted in ≈25% exposure increase in the 75-mg group. Higher exposure was not associated with reduced stroke risk in patients with AF with high renal clearance.

An Open-Label Crossover Study of the Pharmacokinetics of the 60-mg Edoxaban Tablet Crushed and Administered Either by a Nasogastric Tube or in Apple Puree in Healthy Adults.

BACKGROUND: Edoxaban is an orally active, direct factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation and for the treatment of venous thromboembolism. OBJECTIVES: This study assessed the pharmacokinetics, safety, and tolerability of the edoxaban 60-mg tablet crushed and administered via a nasogastric tube in a water suspension or orally mixed in apple puree. METHODS: This phase 1, open-label, crossover study randomized 30 healthy adults to receive three edoxaban treatment regimens (oral 60-mg edoxaban tablet, or 60-mg edoxaban tablet crushed and administered via a nasogastric tube or orally in apple puree) in one of six treatment sequences. RESULTS: Total edoxaban exposure was similar between the intact and crushed tablet regimens (mean area under the plasma concentration-time curve from time zero to infinity: whole tablet, 2132 ng·h/mL; nasogastric tube, 2021 ng·h/mL; apple puree, 2076 ng·h/mL). Mean maximum plasma concentration, area under the plasma concentration-time curve from time zero to the time of the last measurable concentration, terminal half-life, and apparent total body clearance values were also similar. Time to maximum plasma concentration was significantly shorter for the nasogastric tube suspension and apple puree vs. the whole tablet [Hodges-Lehmann estimate of median difference (90% confidence interval): -0.75 (-1.25, -0.28); p = 0.0003 and -0.62 (-0.99, -0.26); p = 0.0024, respectively]. The maximum plasma concentation, area under the plasma concentration-time curve from time zero to infinity, and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration were similar between treatment regimens; 90% confidence interval of the geometric least-squares means ratios were within the predefined 80-125% bioequivalence criterion. The safety and tolerability of edoxaban did not differ between treatment regimens. CONCLUSION: The results support the use of edoxaban tablets crushed and administered either via a nasogastric tube or orally mixed in apple puree in patients who are unable to swallow solid oral dose formulations.

Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL4 receptor.

PURPOSE: For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response. METHODS: Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients. RESULTS: The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0 mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03 L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured. CONCLUSION: The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure.

A phase 2 randomized, double-blind study of AMG 108, a fully human monoclonal antibody to IL-1R, in patients with rheumatoid arthritis.

INTRODUCTION: Preclinical work has suggested that IL-1 plays a critical role in the pathogenesis of rheumatoid arthritis (RA). The objective of the present study was to determine the effect of a long-acting IL-1 receptor inhibitor, AMG 108, in a double-blind, placebo-controlled, parallel-dosing study in patients with active RA who were receiving stable methotrexate (15 to 25 mg/week). METHODS: Patients were randomized equally to receive placebo or 50, 125, or 250 mg AMG 108 subcutaneously every 4 weeks for 6 months. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response (ACR20) at week 24; other efficacy endpoints included the ACR50, the ACR70, and the RA disease activity score (28-joint count Disease Activity Score) responses, patient-reported outcomes, and pharmacokinetic parameters. Safety endpoints included treatment-emergent adverse events (AEs), infectious AEs, serious AEs, serious infections, injection site reactions, laboratory abnormalities, and antibodies to AMG 108. RESULTS: Of 813 patients enrolled in the study, 204 patients were randomized to the 50 mg group, 203 to the 125 mg group, 203 to the 250 mg group, and 203 to placebo. At week 24, 40.4% of the 250 mg group, 36% of the 125 mg group, 30.9% of the 50 mg group, and 29.1% of the placebo group achieved an ACR20 (P = 0.022, 250 mg vs. placebo). Of the individual ACR components, numerical dose-dependent improvements were only seen in tender joint counts, pain (visual analog scale), and the acute phase reactants, erythrocyte sedimentation rate and C-reactive protein. No dose-related increase was observed in the incidence of treatment-emergent AEs. No deaths were reported, and the incidence of AEs and infections, serious AEs and infections, and withdrawals from study for safety were similar in the AMG 108 and placebo groups. CONCLUSIONS: This large double-blind randomized trial with a long-acting IL-1 receptor blocker, AMG 108, is consistent with the experience of other IL-1 blockers, represents a definitive experiment showing that IL-1 inhibition provides only moderate symptomatic amelioration of arthritis activity in the majority of RA patients, and provides an answer to a question that has been discussed for many years in the rheumatologic community. TRIAL REGISTRATION: ClinicalTrials.gov NCT00293826.

Pharmacokinetic and pharmacodynamic modeling of a monoclonal antibody antagonist of glucagon receptor in male ob/ob mice.

Elevated basal concentrations of glucagon and reduced postprandial glucagon suppression are partly responsible for the increased hepatic glucose production seen in type 2 diabetic patients. Recently, it was demonstrated that an antagonistic human monoclonal antibody (mAb) blocking glucagon receptor (GCGR) has profound glucose-lowering effects in various animal models. To further understand the effects on glucose homeostasis mediated by such an antibody, a pharmacokinetic-pharmacodynamic (PK-PD) study was conducted in a diabetic ob/ob mouse model. Four groups of ob/ob mice were randomized to receive single intraperitoneal administration of placebo, 0.6, 1, or 3 mg/kg of mAb GCGR, a fully human mAb against GCGR. The concentration-time data were used for noncompartmental and compartmental analysis. A semi-mechanistic PK-PD model incorporating the glucose-glucagon inter-regulation and the hypothesized inhibitory effect of mAb GCGR on GCGR signaling pathway via competitive inhibition was included to describe the disposition of glucose and glucagon over time. The pharmacokinetics of mAb GCGR was well characterized by a two-compartment model with parallel linear and nonlinear saturable eliminations. Single injection of mAb GCGR caused a rapid glucose-lowering effect with blood glucose concentrations returning to baseline by 4 to 18 days with increasing dose from 0.6 to 3 mg/kg. Elevation of glucagon concentrations was also observed in a dose-dependent manner. The results illustrated that the feedback relationship between glucose and glucagon in the presence of mAb GCGR could be quantitatively described by the developed model. The model may provide additional understanding in the underlying mechanism of GCGR antagonism by mAb.

Approximations of the target-mediated drug disposition model and identifiability of model parameters.

Models for drugs exhibiting target-mediated drug disposition (TMDD) play an important role in the investigation of biological products (Mager and Jusko 2001). These models are often overparameterized and difficult to converge. A simpler quasi-equilibrium (QE) approximation of the general model has been suggested (Mager and Krzyzanski 2005), but even this simpler form can be overparameterized when, for example, drug target level is not available. This work (a) introduces quasi-steady-state (QSS) and Michaelis-Menten (MM) approximations of the TMDD model, (b) derives the relationships between the parameters of the TMDD, QE, QSS and MM models, (c) investigates the parameter ranges where the simplified approximations are equivalent to the TMDD model, (d) proposes an algorithm for establishing identifiability of these models, and (e) tests this algorithm on simulated datasets. The proposed QSS approximation is more general than the QE approximation: it degenerates into the QE approximation when the internalization rate of the drug-target complex is much smaller than its dissociation rate. The proposed identifiability analysis algorithm may be applied to provide justification for use of simplified approximations, avoiding use of incorrect parameter estimates of over-parameterized TMDD models while simultaneously saving time and resources required for the pharmacokinetics analysis of drugs with TMDD. The utility of the derived approximations and of the identifiability algorithm was demonstrated on the examples of the simulated data sets. The simulation examples indicated that the QSS model may be preferable to the QE model when the internalization rate of the drug-target complex significantly exceeds its dissociation rate. The MM approximation may be adequate when the drug concentration significantly exceeds the target concentrations or when the target occupancy is close to 100%.

Pharmacokinetics and safety of a fully human hepatocyte growth factor antibody, AMG 102, in cynomolgus monkeys.

PURPOSE: AMG 102, a fully human monoclonal antibody that binds to hepatocyte growth factor (HGF), is a potential cancer therapeutic agent because of its ability to disrupt HGF/c-Met signaling pathways which have been implicated in most tumor types. To support a phase 1 study, the pharmacokinetic and safety profile of AMG 102 was assessed in cynomolgus monkeys. MATERIALS AND METHODS: Serum concentration-time data from single- (i.v. and s.c.) and repeated-dose (i.v.) studies of up to 13 weeks were used for pharmacokinetic analysis. Safety was assessed in a single-dose safety pharmacology study with i.v. doses of 0 (vehicle), 25, 100, or 300 mg/kg and a 4-week toxicity study with once weekly i.v. doses of 0 (vehicle), 5, 25, or 100 mg/kg. RESULTS: AMG 102 exhibited linear pharmacokinetics over a 600-fold dose range (0.5 to 300 mg/kg) with a mean terminal half-life of 5.6 days after i.v. dosing. Clearance and volume of distribution at steady state were 1.22 ml/h and 198.3 ml, respectively. Estimated bioavailability was 72% for s.c. administration. Antibody response to AMG 102 was observed in a small percentage of monkeys. No treatment-related cardiovascular, respiratory, or CNS changes were observed. Administration of AMG 102 for 4 weeks was well tolerated at doses up to 100 mg/kg. Potential treatment-related effects were limited to minimal/moderate gastric mucosa hemorrhage in the mid- and high-dose groups. CONCLUSIONS: The nonclinical pharmacokinetic and safety profile of AMG 102 effectively supports clinical investigation.

Administration of an antagonist of neurokinin receptors 1, 2, and 3 results in reproductive tract changes in beagle dogs, but not rats.

SCH 206272, an antagonist of neurokinin receptors 1, 2, and 3, was administered orally by gavage for 1 month to 8- to 10-month-old dogs at doses of 0, 15, 30, or 60 mg/kg, and to 6-week-old rats at doses of 0, 30, 100, or 300 mg/kg. The most important changes occurred in the reproductive tract of the dogs at all doses. Absolute and relative group mean organ weights for the testes, prostate gland, epididymides, ovaries, and uterus were 33-86% lower than concurrent controls in groups receiving SCH 206272. Organ weight changes were not dose-related. Microscopic changes that correlated with the organ weight changes occurred in all groups receiving SCH 206272. For males, they included minimal to severe atrophy of the testes, epididymides, and prostate gland. In addition, the epididymides exhibited severe oligospermia or aspermia, minimal epithelial apoptosis and mild epithelial vacuolation. In female dogs, the ovaries and uteri appeared immature. Microscopic changes were similar in incidence and severity in dogs receiving 30 or 60 mg/kg, but were slightly less in dogs receiving 15 mg/kg. In contrast, similar findings were not observed in the reproductive tract of male or female rats, despite overlapping systemic, hypothalamic, and pituitary gland concentrations of SCH 206272.