Pharmacokinetics and Safety of the Tyrosine Kinase 2 Inhibitor Deucravacitinib in Healthy Chinese Subjects.

INTRODUCTION: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, blocks cytokine signaling involved in psoriasis pathogenesis. This ethnic-bridging study evaluated deucravacitinib pharmacokinetics, tolerability, and safety in healthy Chinese subjects. METHODS: This phase I, double-blind, single-/multiple-dose study randomized healthy Chinese subjects 4:1 to a single dose of deucravacitinib 6 mg or placebo (group 1) or deucravacitinib 12 mg or placebo (group 2) on day 1; groups 1 and 2 received deucravacitinib 6 mg and 12 mg once daily, respectively, or placebo on days 5-19. Blood samples were collected on days 1-5 (0 predose-96 h postdose), day 5 (0-24 h postdose), days 9 and 12 (0 h), and day 19 (0-24 h postdose). Deucravacitinib and metabolite (BMT-153261, BMT-158170) concentrations were determined using liquid chromatography/mass spectrometry; pharmacokinetic parameters were calculated using noncompartmental analysis. Urine was collected on days 1-4 (4 h predose-96 h postdose). Safety was monitored throughout. RESULTS: Forty healthy Chinese subjects (groups 1 and 2: deucravacitinib, n = 32; placebo, n = 8) were enrolled. Deucravacitinib was rapidly absorbed after single-/multiple-dose administration, with median time to maximal plasma concentration of 1.5-2.3 h. Systemic exposure after single or multiple doses increased approximately twofold with twofold dose increase. Modest deucravacitinib accumulation was observed after multiple-dose administration (1.3- to 1.4-fold increase in area under the curve [AUC] under one dosing interval). Metabolite-to-parent ratios for maximal plasma concentration and AUC remained consistent in each dose group. Mean urinary percent recovery and renal clearance were similar between dose groups. Most adverse events (AEs) were mild/moderate, with no serious treatment-related AEs, deaths, or discontinuations due to AEs. CONCLUSION: Deucravacitinib was safe and well tolerated in healthy Chinese subjects. Deucravacitinib exhibited rapid absorption, dose-related increases in exposure, comparable half-life, and no evidence of time-dependent pharmacokinetics, suggesting minimal effect of Chinese ethnicity on deucravacitinib pharmacokinetics. CLINICAL TRIAL REGISTRATION: NCT03956953.

Deucravacitinib, a new oral medication, blocks an enzyme called tyrosine kinase 2 (TYK2), which is activated in plaque psoriasis. This reduces thick, scaly patches of skin, itching, and other symptoms. How a drug is absorbed and its effects can vary between patients of different races and ethnicities. We studied the safety of deucravacitinib in healthy Chinese volunteers. We also studied how bigger or smaller doses of deucravacitinib change how much of it is absorbed into the blood. We found that most side effects of deucravacitinib were mild or moderate compared to volunteers taking placebo, a look-alike pill that contains no drug. The most common side effects were skin rashes and headaches. No serious side effects were related to deucravacitinib. Deucravacitinib was quickly absorbed into the blood. The time it took for deucravacitinib to reach its maximum amount in the blood was similar regardless of how large of a dose was initially taken. Increasing the amount of deucravacitinib taken also increased the total amount of deucravacitinib absorbed, both in terms of the total amount absorbed and the maximum amount in blood at one time. These results in healthy Chinese volunteers were similar to the results of other studies in a general population of many races and ethnicities. Deucravacitinib works the same in Chinese patients as in patients of other ethnicities. Chinese patients will not need to adjust their dose when taking deucravacitinib.

First-in-human study of deucravacitinib: A selective, potent, allosteric small-molecule inhibitor of tyrosine kinase 2.

This randomized, double-blind, single- and multiple-ascending dose study assessed the pharmacokinetics (PKs), pharmacodynamics, and safety of deucravacitinib (Sotyktu™), a selective and potent small-molecule inhibitor of tyrosine kinase 2, in 100 (75 active, 25 placebo) healthy volunteers (NCT02534636). Deucravacitinib was rapidly absorbed, with a half-life of 8-15 h, and 1.4-1.9-fold accumulation after multiple dosing. Deucravacitinib inhibited interleukin (IL)-12/IL-18-induced interferon (IFN)γ production ex vivo in a dose- and concentration-dependent manner. Following in vivo challenge with IFNα-2a, deucravacitinib demonstrated dose-dependent inhibition of lymphocyte count decreases and expression of 53 IFN-regulated genes. There were no serious adverse events (AEs); the overall frequency of AEs was similar in the deucravacitinib (64%) and placebo (68%) groups. In this first-in-human study, deucravacitinib inhibited IL-12/IL-23 and type I IFN pathways in healthy volunteers, with favorable PK and safety profiles. Deucravacitinib is a promising therapeutic option for immune-mediated diseases, including Crohn's disease, psoriasis, psoriatic arthritis, and systemic lupus erythematosus.

Lack of Electrocardiographic Effects of Deucravacitinib in Healthy Subjects.

Deucravacitinib is a novel, oral, selective inhibitor of the intracellular signaling kinase tyrosine kinase 2. This phase 1, randomized, partially double-blind, 4-period crossover study in healthy adults was conducted to determine whether deucravacitinib 12 mg (therapeutic dose) or 36 mg (supratherapeutic dose) had a clinically relevant effect on the corrected QT interval and other electrocardiographic (ECG) parameters. Subjects received 1 of 4 sequences of placebo, deucravacitinib 12 mg, deucravacitinib 36 mg, and moxifloxacin 400 mg (positive control) in a randomized crossover fashion. The placebo-corrected change from baseline for the QT interval corrected for heart rate using the Fridericia method (QTcF), ECG parameters, and safety measures were evaluated. A clinically meaningful QTcF prolongation of >10 milliseconds was not found for deucravacitinib at tested doses. Assay sensitivity was demonstrated by the observation of known QT effects of moxifloxacin in the study. Deucravacitinib had no clinically relevant effect on other parameters and was generally well tolerated. The majority of adverse events (AEs) were mild, and all AEs resolved by study's end. Three treatment-related serious AEs of pharyngitis, cellulitis, and lymphadenopathy occurred in 1 subject following administration of deucravacitinib 12 mg, but resolved by end of study. This study demonstrated that a single oral dose of deucravacitinib 12 or 36 mg did not produce a clinically relevant effect on the corrected QT interval or other measured ECG parameters in healthy adults.

Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors.

INTRODUCTION: Deucravacitinib, a novel, oral, selective inhibitor of tyrosine kinase 2 (TYK2) signaling, acts via an allosteric mechanism by binding to the enzyme's regulatory domain instead of the catalytic domain. This unique binding provides high functional selectivity for TYK2 versus the closely related Janus kinases (JAKs) 1/2/3. Deucravacitinib was efficacious in phase 2 and 3 psoriasis trials, without clinical or laboratory parameters indicative of JAK 1/2/3 inhibition being observed. This analysis compared the kinase specificities of deucravacitinib versus JAK 1/2/3 inhibitors at therapeutic exposures. METHODS: Signaling via JAK 1/3, JAK 2/2, and TYK2/JAK 2 dimers was measured in in vitro whole blood assays. Concentrations providing half-maximal inhibition (IC50) in these assays were determined for deucravacitinib and the JAK 1/2/3 inhibitors tofacitinib, upadacitinib, and baricitinib. Newly derived whole blood IC50 values were plotted against available pharmacokinetic profiles using doses evaluated in phase 2/3 trials. Simulated average daily inhibition and durations over which concentrations exceeded IC50 were evaluated. RESULTS: At clinically relevant exposures, projected steady-state deucravacitinib plasma concentrations were higher than TYK2 IC50 for approximately 9-18 h. Maximal plasma concentrations (Cmax) of deucravacitinib were 8- to 17-fold lower than JAK 1/3 IC50 and > 48- to > 102-fold lower than JAK 2/2 IC50. Simulated daily average TYK2 inhibition by deucravacitinib ranged from 50% to 69%. Simulations indicated that tofacitinib, upadacitinib, and baricitinib at steady state exhibited varying degrees of JAK 1/3 (daily average inhibition, 70-94%) and JAK 2/2 (23%-67%) inhibition at therapeutic concentrations, with Cmax values 17- to 33-fold lower than their TYK2 IC50 levels. CONCLUSION: At clinically relevant doses and exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 and not JAK 1/2/3. Tofacitinib, upadacitinib, and baricitinib variably inhibit JAK 1/2/3 but not TYK2. These results indicate that deucravacitinib is a distinct class of kinase inhibitor compared with JAK 1/2/3 inhibitors.

Psoriasis is a common, chronic inflammatory skin condition that impairs patients' physical health, emotional well-being, work performance, and overall quality of life. Psoriasis and related conditions such as psoriatic arthritis are caused by abnormalities in the immune system. Various drugs are used or explored to treat these conditions, including Janus kinase (JAK) inhibitors; however, JAK inhibitors are associated with a range of side effects such as abnormal changes in blood cell, cholesterol, and triglyceride levels, as well as liver and kidney dysfunction. Deucravacitinib is a new oral drug in development that blocks a key molecule involved in the pathogenesis of psoriasis known as tyrosine kinase 2 (TYK2). This analysis compared the selectivity of deucravacitinib versus approved JAK 1/2/3 inhibitors (tofacitinib, upadacitinib, and baricitinib) for TYK2 and JAK 1/2/3 in whole blood assays, using therapeutic doses of each drug. The authors reported that deucravacitinib inhibits TYK2 with minimal or no inhibition of JAK 1/2/3. In contrast, tofacitinib, upadacitinib, and baricitinib inhibit JAK 1, JAK 2, and/or JAK 3 to various degrees but do not inhibit TYK2. These results demonstrate that deucravacitinib is a distinct class of drug compared with the JAK 1/2/3 inhibitors. The results of this analysis are consistent with those of two recently completed phase 3 trials in patients with moderate-to-severe plaque psoriasis (POETYK PSO-1 and PSO-2), as well as a phase 2 trial in psoriasis, in which deucravacitinib was efficacious and well tolerated, without clinical or laboratory abnormalities suggestive of JAK 1/2/3 inhibition being observed.

Population Pharmacokinetic Analysis of BMS-986166, a Novel Selective Sphingosine-1-Phosphate-1 Receptor Modulator, and Exposure-Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants.

Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS-986166, a prodrug of the active phosphorylated metabolite BMS-986166-P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS-986166 versus placebo after single (0.75-5.0 mg) and repeated (0.25-1.5 mg/day) oral administration were assessed in healthy participants after a 1-day lead-in placebo period. A population model was developed to jointly describe BMS-986166 and BMS-986166-P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS-986166-P concentrations and nadir of time-matched (day -1) placebo-corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo.

The safety and pharmacokinetics of a novel, selective S1P1R modulator in healthy participants.

Background: Safety, pharmacokinetics and pharmacodynamics of BMS-986166, a novel sphingosine-1-phosphate receptor 1 modulator, were assessed.Research design and methods: Two double-blind, placebo-controlled, randomized Phase l studies were conducted in healthy participants. In the single ascending dose study (N = 70), BMS-986166 was administered as a single dose, upwardly titrated daily doses or a single dose in participants who were fed, fasted or administered famotidine. In the multiple ascending dose study (N = 32), BMS-986166 was administered daily for 28 days. Safety, pharmacokinetics and pharmacodynamics (absolute lymphocyte count [ALC]) were assessed.Results: BMS-986166 was generally well tolerated; treatment-related adverse events were mild. Dose-related, clinically insignificant reductions in time-matched heart rate were recorded versus placebo. Pharmacokinetics were linear and stationary with approximately dose-related increases in blood exposure of BMS-986166. Decreases in ALC percent change from baseline with multiple doses of BMS-986166 versus placebo were dose-related. Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14-21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg.Conclusions: BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711.

Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS-986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo-controlled trial in healthy participants.

AIMS: Branebrutinib (BMS-986195) is a potent, highly selective, oral, small-molecule, covalent inhibitor of Bruton's tyrosine kinase (BTK). This study evaluated safety, pharmacokinetics and pharmacodynamics of branebrutinib in healthy participants. METHODS: This double-blind, placebo-controlled, single- and multiple-ascending dose (SAD; MAD) Phase I study (NCT02705989) enrolled participants into 3 parts: SAD, MAD and JMAD (MAD in first-generation Japanese participants). In each part, participants were randomised 3:1 to receive branebrutinib (SAD: 0.3-30 mg; [J]MAD: 0.3-10 mg) or placebo. Participants in the MAD parts received branebrutinib daily for 14 days and were followed for 14 days postdosing. Safety was assessed by monitoring, laboratory and physical examinations, vital signs, and recording adverse events (AEs). Pharmacodynamics were assessed with a mass spectrometry assay that measured drug-occupied and free BTK. RESULTS: The SAD, MAD and JMAD parts of the study included 40, 32 and 24 participants. Branebrutinib was well tolerated and AEs were mild/moderate, except for 1 serious AE that led to discontinuation. Branebrutinib was rapidly absorbed, with maximum plasma concentration occurring within 1 hour and a half-life of 1.2-1.7 hours, dropping to undetectable levels within 24 hours. BTK occupancy was rapid, with 100% occupancy reached after a single 10-mg dose. BTK occupancy decayed predictably over time (mean half-life in MAD panels: 115-154 hours), such that pharmacodynamic effects were maintained after branebrutinib plasma levels fell below the lower limit of quantification. CONCLUSION: Rapid and high occupancy of BTK and the lack of notable safety findings support further clinical development of branebrutinib.

Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab.

PURPOSE: Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis. METHODS: Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/µL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters. RESULTS: Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase. CONCLUSIONS: In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any 'cytokine storm'. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT02960854.

Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 Antibody (BMS-936559).

OBJECTIVES: To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression. DESIGN: Randomized, placebo-controlled, dose-escalation. SETTING: Seven U.S. hospital ICUs. STUDY POPULATION: Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/µL. INTERVENTIONS: Participants received single-dose BMS-936559 (10-900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels. MEASUREMENTS AND MAIN RESULTS: The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1-2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1-2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days. CONCLUSIONS: In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis.

Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis.

BACKGROUND: Tyrosine kinase 2 (TYK2) signaling pathways, which mediate cytokine signaling, are implicated in the pathophysiology of psoriasis. Selective inhibitors of TYK2 may be effective in treating psoriasis. METHODS: We conducted a phase 2, double-blind trial of a TYK2 inhibitor, BMS-986165, in adults with moderate-to-severe psoriasis, excluding patients with a previous lack of response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Patients were randomly assigned to receive the drug orally at a dose of 3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily or to receive placebo. The primary end point was a 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (higher scores indicate greater severity of psoriasis). RESULTS: A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75% or greater reduction in the PASI score was 7% (3 of 45 patients) with placebo, 9% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P=0.49 vs. placebo), 39% (17 of 44 patients) with 3 mg daily (P<0.001 vs. placebo), 69% (31 of 45 patients) with 3 mg twice daily (P<0.001 vs. placebo), 67% (30 of 45 patients) with 6 mg twice daily (P<0.001 vs. placebo), and 75% (33 of 44 patients) with 12 mg daily (P<0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment. CONCLUSIONS: Selective inhibition of TYK2 with the oral agent BMS-986165 at doses of 3 mg daily and higher resulted in greater clearing of psoriasis than did placebo over a period of 12 weeks. Larger and longer-duration trials of this drug are required to determine its safety and durability of effect in patients with psoriasis. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02931838 .).

Pharmacokinetic-pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age.

PURPOSE: To identify and validate the efficacious monotherapy dosing regimen for topiramate in children aged 2 to <10 years with newly diagnosed epilepsy using pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation bridging. METHODS: Several models were developed in pediatric and adult populations to relate steady-state trough plasma concentrations (C(min)) of topiramate to the magnitude of clinical effect in monotherapy and adjunctive settings. These models were integrated to derive and support the monotherapy dosing regimen for pediatric patients. KEY FINDINGS: A two-compartmental population PK model with first-order absorption described the time course of topiramate C(min) as a function of dosing regimen. Disposition of topiramate was related to age, body weight, and use of various concomitant antiepileptic drugs. The PK-PD model for monotherapy indicated that the hazard of time to first seizure decreased with increasing C(min) and time since randomization. Higher baseline seizure frequency increased risk for seizures. Age did not significantly influence hazard of time to first seizure after randomization to monotherapy. For adjunctive therapy, the distribution of drug and placebo responses was not significantly different among age groups. Based on the available PK-PD modeling data, the dosing regimen expected to achieve a 65-75% seizure freedom rate after 1 year for pediatric patients age 2-10 years is approximately 6-9 mg/kg per day. SIGNIFICANCE: This analysis indicated no difference in PK-PD of topiramate between adult and pediatric patients. Effects of indication and body weight on PK were adequately integrated into the model, and monotherapy dosing regimens were identified for children 2-10 years of age.

Population pharmacodynamic parameter estimation from sparse sampling: effect of sigmoidicity on parameter estimates.

The objective of this stimulation study was to evaluate effect of simoidicity of the concentration-effect (C-E) relationship on the efficiency of population parameter estimation from sparse sampling and is a continuation of previous work that addressed the effect of sample size and number of samples on parameters estimation from sparse sampling for drugs with C-E relationship characterized by high sigmoidicity (gamma > 5). The findings are based on observed C-E relationships for two drugs, octreotide and remifentanil, characterized by simple E (max) and sigmoid E (max) models (gamma = ~2.5), respectively. For each model, C-E profiles (100 replicates of 100 subjects each) were simulated for several sampling designs, with four or five samples/individual randomly obtained from within sampling windows based on EC(50)-normalized plasma drug concentrations, PD parameters based on observed population mean values, and inter-individual and residual variability of 30% and 25%, respectively. The C-E profiles were fitted using non-linear mixed effect modeling with the first-order conditional estimation method; variability parameters were described by an exponential error model. The results showed that, for the sigmoid E (max) model, designs with four or five samples reliably estimated the PD parameters (EC(50), E (max), E (0), and gamma), whereas the five-sample design, with two samples in the 2-3 E (max) region, provided in addition more reliable estimates of inter-individual variability; increasing the information content of the EC(50) region was not critical as long as this region was covered by a single sample in the 0.5-1.5 EC(50) window. For the simple E (max) model, because of the shallower profile, enriching the EC(50) region was more important. The impact of enrichment of appropriate regions for the two models can be explained based on the shape (sigmoidicity) of the concentration-effect relationships, with shallower C-E profiles requiring data enrichment in the EC(50) region and steeper curves less so; in both cases, the E (max) region needs to be adequately delineated, however. The results provide a general framework for population parameter estimation from sparse sampling in clinical trials when the underlying C-E profiles have different degrees of sigmoidicity.

Pharmacodynamic parameter estimation: population size versus number of samples.

The purpose of this study was to evaluate the effects of population size, number of samples per individual, and level of interindividual variability (IIV) on the accuracy and precision of pharmacodynamic (PD) parameter estimates. Response data were simulated from concentration input data for an inhibitory sigmoid drug efficacy (E(max)) model using Nonlinear Mixed Effect Modeling, version 5 (NONMEM). Seven designs were investigated using different concentration sampling windows ranging from 0 to 3 EC(50) (EC(50) is the drug concentration at 50% of the E(max)) units. The response data were used to estimate the PD and variability parameters in NONMEM. The accuracy and precision of parameter estimates after 100 replications were assessed using the mean and SD of percent prediction error, respectively. Four samples per individual were sufficient to provide accurate and precise estimate of almost all of the PD and variability parameters, with 100 individuals and IIV of 30%. Reduction of sample size resulted in imprecise estimates of the variability parameters; however, the PD parameter estimates were still precise. At 45% IIV, designs with 5 samples per individual behaved better than those designs with 4 samples per individual. For a moderately variable drug with a high Hill coefficient, sampling from the 0.1 to 1, 1 to 2, 2 to 2.5, and 2.5 to 3 EC(50) window is sufficient to estimate the parameters reliably in a PD study.