Population pharmacokinetic-pharmacodynamic model of oxfendazole in healthy adults in a multiple ascending dose and food effect study and target attainment analysis

Oxfendazole is a potent veterinary antiparasitic drug undergoing development for human use to treat multiple parasitic infections. Results from two recently completed Phase I clinical trials conducted in healthy adults showed that the pharmacokinetics of oxfendazole is nonlinear, affected by food, and, after the administration of repeated doses, appeared to mildly affect hemoglobin concentrations. To facilitate oxfendazole dose optimization for its use in patient populations, the relationship among oxfendazole dose, pharmacokinetics and hemoglobin concentration was quantitatively characterized using population pharmacokinetic-pharmacodynamic modeling. In fasting subjects, oxfendazole pharmacokinetics was well described by a one-compartment model with first-order absorption and elimination. The change in oxfendazole pharmacokinetics when administered following a fatty meal was captured by an absorption model with one transit compartment and increased bioavailability. The effect of oxfendazole exposure on hemoglobin concentration in healthy adults was characterized by a lifespan indirect response model in which oxfendazole has positive but minor inhibitory effect on red blood cell synthesis. Further simulation indicated that oxfendazole has a low risk of posing a safety concern regarding hemoglobin concentration, even at a high oxfendazole dose of 60 mg/kg once daily. The final model was further used to perform comprehensive target attainment simulations for whipworm infection and filariasis at various dose regimens and target attainment criteria. The results of our modeling work, when adopted appropriately, have the potential to greatly facilitate oxfendazole dose regimen optimization in patient populations with different types of parasitic infections.

Ustekinumab Dosing Individualization in Crohn’s Disease Guided by a Population Pharmacokinetic–Pharmacodynamic Model

Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.

Pharmacokinetic-Pharmacodynamic Modelling of Systemic IL13 Blockade by Monoclonal Antibody Therapy: A Free Assay Disguised as Total

A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled per cohort. Eight volunteers received placebo as control. Following single subcutaneous administration (SC), individual time courses of serum MEDI7836 concentrations, and the resulting serum IL13 modulation in vivo, were quantified. A binding pharmacokinetic-pharmacodynamic (PK-PD) indirect response model was built to characterize the exposure-driven modulation of the target over time by MEDI7836. While the validated bioanalytical assay specification quantified the level of free target (i.e., a free IL13 assay), emerging clinical data suggested dose-dependent increase in systemic IL13 concentration over time, indicative of a total IL13 assay. The target time course was modelled as a linear combination of free target and a percentage of the drug-target complex to fit the clinical data. This novel PK-PD modelling approach integrates independent knowledge about the assay characteristics to successfully elucidate apparently complex observations.

Modeling and Simulation to Support Phase Ib/IIa Dose Selection for WBP216, A Long Half-Life Fully Human Monoclonal Antibody Against Interleukin-6

WBP216 is an innovative IL-6 antibody, presenting high affinity to IL-6 and a long half-life (40–60 days). To optimize the dosage regimen for future clinical trials, pharmacokinetics (PK) and pharmacodynamics (PD) of WBP216 would be firstly characterized in Chinese rheumatoid arthritis (RA) patients. PK, CRP and DAS28 data of WBP216 were collected from 26 RA patients in a single ascending dose study. Non-linear mixed effects modeling was used for a population PK/PD analysis. A two-compartment model with a sequential zero-first order absorption and a first order elimination best described PK behavior of WBP216. Apparent systemic clearance was 0.015 L/h, central volume was 8.04 L. CRP as the fast-decreasing endpoint and DAS28 as the slow-reacting endpoint were both fitted well through an indirect response model. The baseline of ALT and free IL-6 were found associated with PK/PD parameters during covariates exploration. Simulation results confirmed that a loading dose regimen either of administration at weeks 0, 2, and 6 or doubling the maintenance dose level, followed by maintenance dosing of 75–150 mg every 8 weeks, was expected to provide a best risk/benefit ratio in future clinical studies. We hope this first PK/PD study of WBP216 in Chinese RA patients will help in the clinical development of WBP216 in future and provide a reference to the dosage optimization of similar antibodies with long half-life.Clinical Trial Registration:CTR20170306

Exposure-Response and Clinical Outcome Modeling of Inhaled Budesonide/Formoterol Combination in Asthma Patients

Exposure-response and clinical outcome (CO) model for inhaled budesonide/formoterol was developed to quantify the relationship among pharmacokinetics (PK), pharmacodynamics (PD) and CO of the drugs and evaluate the covariate effect on model parameters. Sputum eosinophils cationic proteins (ECP) and forced expiratory volume (FEV1) were selected as PD markers and asthma control score was used as a clinical outcome. One- and two-compartment models were used to describe the PK of budesonide and formoterol, respectively. The indirect response model (IDR) was used to describe the PD effect for ECP and FEV1. In addition, the symptomatic effect on the disease progression model for CO was connected with IDR on each PD response. The slope for the effect of ECP and FEV1 to disease progression were estimated as 0.00008 and 0.644, respectively. Total five covariates (ex. ADRB2 genotype etc.) were searched using a stepwise covariate modeling method, however, there was no significant covariate effect. The results from the simulation study were showed that a 1 puff b.i.d. had a comparable effect of asthma control with a 2 puff b.i.d. As a result, the 1 puff b.i.d. of combination drug could be suggested as a standardized dose to minimize the side effects and obtain desired control of disease compared to the 2 puff b.i.d.

Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy

Oxaliplatin (L-OHP) is widely prescribed for treating gastroenterological cancer. L-OHP-induced peripheral neuropathy is a critical toxic effect that limits the dosage of L-OHP. An ideal chemotherapeutic strategy that does not result in severe peripheral neuropathy but confers high anticancer efficacy has not been established. To establish an optimal evidence-based dosing regimen, a pharmacokinetic-toxicodynamic (PK-TD) model that can characterize the relationship between drug administration regimen and L-OHP-induced peripheral neuropathy is required. We developed a PK-TD model of L-OHP for peripheral neuropathy using Phoenix® NLME™ Version 8.1. Plasma concentration of L-OHP, the number of withdrawal responses in the acetone test, and the threshold value in the von Frey test following 3, 5, or 8 mg/kg L-OHP administration were used. The PK-TD model consisting of an indirect response model and a transit compartment model adequately described and simulated time-course alterations of onset and grade of L-OHP-induced cold and mechanical allodynia. The results of model analysis suggested that individual fluctuation of plasma L-OHP concentration might be a more important factor for individual variability of neuropathy than cell sensitivity to L-OHP. The current PK-TD model might contribute to investigation and establishment of an optimal dosing strategy that can reduce L-OHP-induced neuropathy.

Modeling of pharmacodynamic (PD) biomarkers (BM) related to CDK4/6 inhibition and exploratory BM-response (progression free survival [PFS]) analyses in patients with advanced breast cancer.

e14528 Background: Palbociclib (PAL) is an oral inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6) approved for advanced breast cancer (ABC). In a clinical trial, the expression levels of PD BMs related to PAL effect, including thymidine kinase (TK) in serum and phosphor-Rb (pRb) and Ki67 in skin tissues, were measured at both baseline and post-treatment in patients with ABC treated with PAL plus letrozole (LET). Pharmacokinetic (PK)/PD modeling was conducted previously to characterize the longitudinal change of pRb and Ki67. The PK/PD was further evaluated for TK and exploratory analyses were conducted to evaluate the relationship between PFS and all three BMs. Methods: The present analyses used data from a Phase 1 study evaluating the PK, PD, safety and efficacy of PAL plus LET in 26 Chinese women with ABC. A 2 compartment model was used to describe the PK of PAL. A precursor-dependent indirect response model was developed to describe the TK time course after PAL treatment. PAL effect was modeled as Imax inhibitory model. Cox proportional hazard model was used to assess the correlation of PFS with three BM metrics (baseline BM, simulated lowest BM and maximum BM change in Cycle 1). Results: The BM data included 194 TK observations from 26 patients. The PK/PD models adequately described the longitudinal change of TK, and showed PAL caused TK reduction. The estimated IC50 value was 49.5 ng/mL, similar to those for pRb and Ki67. The BM-response analyses for PFS showed that correlation was found for TK. There was a significant correlation between PFS and baseline TK (BTK) and minimum TK (MTK) in Cycle 1. A longer PFS was associated with lower BTK and lower MTK. A trend for longer PFS with higher maximum TK change in Cycle 1 was observed although the relationship was not statistically significant. Conclusions: PAL exposure had significant correlation with the reduction of all three BMs. Longer PFS was associated with lower BTK and MTK. Due to the small sample size (N = 26), this analyses result need to be confirmed in a larger study.

Temporal delays and individual variation in antidiuretic response to desmopressin

This study aimed to estimate the relationship between pharmacokinetics and the antidiuretic effect of desmopressin. In the investigator-blind, randomized, parallel group study, 5 dose groups and 1 placebo group, each consisting of 12 healthy, overhydrated, nonsmoking male subjects 18–55 yr of age were infused intravenously over 2 h with placebo or 30, 60, 125, 250, and 500 ng desmopressin in 50 ml of normal saline. Plasma desmopressin and urine osmolality rose by variable amounts during the infusions of 60, 125, 250, and 500 ng desmopressin. Plotting mean urine osmolality against the concurrent mean plasma desmopressin yielded a temporal delay between pharmacokinetic (PK) and -dynamic (PD) responses in all dose groups. Using simulation from the indirect-response model, assuming a constant (4 ng/ml) desmopressin concentration, this delay between PK and PD was estimated at 4 h (10th-90th percentile: 1.8–8.1). Within each group, however, there were large individual variations (2- to 10-fold) in the magnitude and duration of the antidiuretic effect. The antidiuretic effect of intravenous desmopressin in water-loaded healthy adults varies considerably due largely to factors other than individual differences in pharmacokinetics. The antidiuretic effect is time as well as dose dependent and may be self-amplifying. The most likely explanation for these findings is that the time required for a given level of plasma desmopressin to exert its maximum antidiuretic effect varies markedly from person to person due to individual differences in the kinetics of one or more of the intracellular mechanisms that promote the reabsorption of solute-free water by principal cells in renal collecting tubules.