Computational design of clinical trials using a combination of simulation and the genetic algorithm.

Artificial intelligence (AI) has come to be used in various technological fields in recent years. However, there have been no reports of AI-designed clinical trials. In this study, we tried to develop study designs by a genetic algorithm (GA), which is an AI solution for combination optimization problems. Specifically, the computational design approach was applied to optimize the blood sampling schedule for a bioequivalence (BE) study in pediatrics and optimize the allocation of dose groups for a dose-finding study. The GA could reduce the number of blood collection points from 15 (typical standard) to seven points without meaningful impact on the accuracy and precision of the pharmacokinetic estimation for the pediatric BE study. For the dose-finding study, up to 10% reduction of the total number of required subjects from the standard design could be achieved. The GA also created a design that would lead to a drastic reduction of the required number of subjects in the placebo arm while keeping the total number of subjects at a minimum level. These results indicated the potential usefulness of the computational clinical study design approach for innovative drug development.

Bridging Efficacy of Tofacitinib Immediate-Release to Extended-Release Formulations for Treatment of Ulcerative Colitis: Application of a Model-Informed Drug Development Approach.

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We report a model-informed drug development approach for bridging efficacy from immediate-release (IR) to extended-release (XR) tofacitinib formulations in patients with UC. IR-XR efficacy bridging was supported by exposure-response analysis of phase 3 induction/maintenance studies of the IR formulation in UC to identify exposure metrics relevant for efficacy. Pharmacokinetic studies in healthy subjects were used to confirm similarity of relevant exposure metrics of tofacitinib IR 5 mg twice daily to XR 11 mg once daily, and tofacitinib IR 10 mg twice daily to XR 22 mg once daily, thereby bridging efficacy between IR and XR formulations. Food effect was evaluated at both XR formulation dose levels. Exposure-response analysis demonstrated that area under the plasma concentration-time curve (average plasma concentration) was a relevant predictor of efficacy. Pharmacokinetic studies demonstrated that area under the plasma concentration-time curve was equivalent between formulations under single-dose and steady-state conditions, and other exposure metrics were also similar. These results also supported bridging of safety data for IR-XR formulations. Food had no impact on tofacitinib XR exposure. These data support efficacy/safety bridging of IR-XR formulations in patients with UC.

Exposure-Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies.

Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis. Relationships between plasma tofacitinib concentration and efficacy were characterized using exposure-response (E-R) models, with demographic and disease covariates evaluated as potential predictors of efficacy. Data were from phase II and III (OCTAVE Induction 1 and 2) induction studies, and a phase III maintenance study (OCTAVE Sustain). Induction studies included 1,355 patients (tofacitinib 0.5, 3, 10, or 15 mg b.i.d. or placebo). The maintenance study included 592 patients (tofacitinib 5 or 10 mg b.i.d. or placebo). E-R models, including induction patients predicted placebo-adjusted remission rates of 6.4% and 12.7% at week 8 for tofacitinib 5 and 10 mg b.i.d., respectively; corresponding rates in patients without prior tumor necrosis factor inhibitor (TNFi) failure were 12.8% and 20.4%. Estimates to achieve/maintain remission at week 52 of maintenance were 29% and 18% (tofacitinib 5 mg b.i.d.), and 41% and 26% (tofacitinib 10 mg b.i.d.), for patients in remission or not following induction, respectively. During maintenance, patients with prior TNFi failure had lower probability of remission on 5 mg b.i.d. (24.9%) than 10 mg b.i.d. (35.0%). Results indicated tofacitinib 10 mg b.i.d. was an appropriate induction dose but suggested efficacy with 5 mg b.i.d. in patients without prior TNFi failure. Tofacitinib 5 mg b.i.d. was efficacious for maintenance, although patients with prior TNFi failure might see additional benefit on 10 mg b.i.d. Per product labeling, recommended tofacitinib induction dose is 10 mg b.i.d., then maintenance at 5 mg b.i.d. For patients who lose response during maintenance, 10 mg b.i.d. may be considered, limited to the shortest duration. Clinicaltrials.gov: NCT00787202; NCT01465763; NCT01458951; and NCT01458574.

Tofacitinib as Induction and Maintenance Therapy in Japanese Patients with Active Ulcerative Colitis.

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor approved in Japan for the treatment of ulcerative colitis (UC). Differences in the safety profile of tofacitinib in Japanese patients versus the global population, such as a higher risk of herpes zoster, have been reported. OBJECTIVES: We conducted post hoc analyses of tofacitinib treatment in Japanese patients with moderate-to-severe UC in two global phase III studies. METHODS: In OCTAVE Induction 1 (NCT01465763), 62 patients were randomized to placebo or tofacitinib 10 mg twice daily (b.i.d.). In OCTAVE Sustain (NCT01458574), 39 patients with clinical response in OCTAVE Induction 1 were re-randomized to placebo, tofacitinib 5 mg, or 10 mg b.i.d. Efficacy endpoints included: remission (primary endpoint; total Mayo score ≤2; no individual subscore >1; rectal bleeding subscore 0); mucosal healing (Mayo endoscopic subscore ≤1); clinical response (≥30% and ≥3-point decrease from induction study baseline total Mayo score; decrease in rectal bleeding subscore ≥1 or absolute subscore ≤1). Adverse events (AEs) and clinical laboratory parameters were recorded. RESULTS: At week 8 of OCTAVE Induction 1, 22.4% of patients achieved remission with tofacitinib (placebo, 7.7%). At week 52 of OCTAVE Sustain, 31.3% and 66.7% of patients receiving tofacitinib 5 and 10 mg b.i.d., respectively, achieved remission (placebo, 9.1%). The occurrence of AEs or serious AEs in Japanese patients was generally similar to that in the global study population, with no new or unexpected safety risks observed. CONCLUSIONS: Although patient numbers were small, tofacitinib demonstrated numerically greater efficacy versus placebo among Japanese patients in OCTAVE Induction 1 and OCTAVE Sustain, with a safety profile consistent with that of the global study population.

Safety and pharmacokinetics of bapineuzumab in a single ascending-dose study in Japanese patients with mild to moderate Alzheimer's disease.

AIM: To evaluate the safety, tolerability and pharmacokinetic profile of bapineuzumab after a single intravenous injection in Japanese patients with mild to moderate Alzheimer's disease. METHODS: Participants received either a placebo (n = 8), or bapineuzumab 0.15 (n = 6), 0.5 (n = 6), 1.0 (n = 6) or 2.0 (n = 6) mg/kg. Serum concentrations of bapineuzumab, antibapineuzumab antibody and total plasma ß-amyloidx-40 were assayed. RESULTS: Adverse events for bapineuzumab and placebo groups were 71% and 88%, respectively. Treatment-emergent adverse events (cataract, injection site hemorrhage, nasopharyngitis, pneumonia and muscle twitching) reported for ≥2 participants were mild or moderate in severity and unrelated to bapineuzumab dose. No deaths, serious adverse events or withdrawals were reported. Mean peak concentration for bapineuzumab increased with dose, from 3.3 ± 0.9 µg/mL with the 0.15 mg/kg dose to 61.0 ± 32.8 µg/mL with 2.0 mg/kg. Mean bapineuzumab exposure (area under the curve from time 0 to last measurable concentration; µg·h/mL) increased in a linear manner with increasing dose (mean 1260 for 0.15 mg/kg, 4264 for 0.5 mg/kg, 7818 for 1.0 mg/kg, 15 313 for 2.0 mg/kg). Mean half-life ranged from 15 to 28 days, and clearance was similar across dose groups (range 0.12-0.17 mL/h/kg). CONCLUSIONS: Plasma ß-amyloidx-40 levels increased with increasing doses of bapineuzumab. Bapineuzumab was safe and well tolerated at all doses in Japanese patients with mild to moderate Alzheimer's disease. Geriatr Gerontol Int 2016; 16: 644-650.

[Population pharmacokinetic analysis of two theophylline formulations in premature neonates and infants with apnea].

A study was conducted to clarify differences in the theophylline pharmacokinetics of two orally available products, theophylline alcohol and Apnecut, in premature neonates and infants using population pharmacokinetic analysis. Fifty-two patients with apnea hospitalized at the National Center for Child Health and Development were enrolled (total number of plasma concentration points=90). Population pharmacokinetic analysis under steady-state conditions was performed using NONMEM ver. V. The mean oral clearance was 0.0249 (l/h), and the inter- and intraindividual variation was 30.3% and 28.3%, respectively, in the basic model. The oral clearance was significantly affected by body weight, sex, and age. The final model obtained was expressed by the following equation: oral clearance (l/h)=0.0201 x (body weight (g)/1000)(1.08)x (1-0.282 x drug product), where theophylline alcohol is 0 and Apnecut is 1. The inter- and intraindividual variations in the final model were 15.0% and 15.3%, respectively. The oral clearance of the two oral formulations differed significantly, and this difference should be considered when adjusting the theophylline dose.

The comparability of etanercept pharmacokinetics in healthy Japanese and American subjects.

Thirty Japanese (J) and 32 American (A) healthy subjects received single doses of etanercept by subcutaneous injection, in 3 separate trials. Serum samples were collected for 480 hours after dosing. Concentrations were determined using enzyme-linked immunosorbent assay methods. Pharmacokinetic parameters were calculated using both non-compartmental and compartmental methods. Etanercept was slowly absorbed, with mean+/-SD time to maximum serum concentration of 47+/-15 hours (J), and 51+/-20 hours (A). The maximum serum concentration and area under the concentration time curve increased for doses 10 mg, 25 mg, and 50 mg, in a linear relationship. Etanercept was slowly eliminated, with observed mean+/-SD half-life of 80+/-25 hours (J) and 75+/-15 hours (A) and mean+/-SD apparent clearance of 144+/-65 mL/h (J) and 132+/-74 mL/h (A). Very low concentrations of etanercept were observed in the urine samples collected in the Japanese subjects. All adverse reactions observed resolved without issue, and none required discontinuation from the study.

Evaluation of Bayesian estimation of pharmacokinetic parameters.

The validity of pharmacokinetic parameters estimated by the maximum a posteriori probability (MAP) Bayesian method was investigated by simulation studies. A 1-compartment model with bolus intravenous administration was used as a pharmacokinetic model, and the coefficients of variation for the parameters and residual error were set at 30% and 10%, respectively. The accuracy of the posterior modes of pharmacokinetic parameters estimated by the MAP Bayesian method was assessed by the difference between the true value and the estimated value. The results showed that the accuracy of the Bayesian estimation depended on sampling times and on the differences between the prior means and individual true parameter values. For assessing the reliability and accuracy of the Bayesian estimation, the authors suggest using the whole posterior distribution of the pharmacokinetic parameters to describe the 95th percentile range for predicted blood concentration profiles. The authors believe that the proposed procedures provide helpful information for evaluating the Bayesian estimation of pharmacokinetic profiles.