Guselkumab is an anti-interleukin-23 human monoclonal antibody effective in treating psoriatic arthritis (PsA). To characterize the pharmacokinetics (PKs) and exposure-response relationship of guselkumab in PsA, population PKs, and exposure-response modeling, analyses were conducted using data from pivotal phase III studies of subcutaneous guselkumab in patients with PsA. The observed serum concentration-time data of guselkumab were adequately described by a one-compartment linear PK model with first-order absorption and elimination. Covariates identified as contributing to the observed guselkumab PK variability were body weight and diabetes comorbidity; however, the magnitude of the effects of these covariates was not considered clinically relevant, and dose adjustment was not warranted for the patient population investigated. Positive exposure-response relationships were demonstrated with landmark and longitudinal exposure-response analyses between guselkumab exposure and clinical efficacy end points (American College of Rheumatology [ACR] 20%, 50%, and 70% improvement criteria and Investigator's Global Assessment [IGA] of psoriasis) at weeks 20 and/or 24, with no clinically relevant differences observed in improvement of PsA signs and symptoms between the two guselkumab treatment regimens evaluated (100 mg every 4 weeks or 100 mg at weeks 0 and 4, then every 8 weeks). Baseline Disease Activity Score in 28 joints (DAS28), Psoriasis Area and Severity Index (PASI) score, and/or C-reactive protein level were identified as influencing covariates on guselkumab exposure-response model parameters. These results provide a comprehensive evaluation of subcutaneous guselkumab PKs and exposure-response relationship that supports the dose regimen of 100 mg at weeks 0 and 4, then every 8 weeks in patients with PsA.

Background and PurposeAntigen‐binding fragment (Fab) reversal agents were developed to reverse, in bleeding emergency, the long‐acting anticoagulant effect of JNJ‐64179375 (JNJ‐9375), a monoclonal antibody that binds exosite‐1 on thrombin.Experimental ApproachThe pharmacokinetic and pharmacodynamic (PK/PD) activities of three reversal agents of varying in vitro binding affinities to JNJ‐9375 were characterised in cynomolgus monkeys. The time course of JNJ‐9375 anticoagulant activity and reversal effects of each agent were evaluated. A mechanism‐based PK/PD model, which integrated free serum concentrations of reversal agent, total and free serum concentrations of JNJ‐9375, and thrombin time, was developed to quantitatively relate JNJ‐9375 neutralisation to reversal of induced thrombin time prolongation. Model‐based allometric scale‐up of the lead reversal agent and the PK/PD relationship of JNJ‐9375 in healthy volunteers were utilised to predict clinical dosing regimens.Key ResultsLowering of free JNJ‐9375 by the reversal agents corresponded with reversal of thrombin time prolongation. Total JNJ‐9375 displayed typical mAb clearance at 2.75 ml·day−1·kg−1, whereas reversal agents cleared faster between 1400 and 2400 ml·day−1·kg−1. The model‐estimated in vivo KD values for JNJ‐9375 reversal agents were 9 nM (ICHB‐256), 0.4 nM (ICHB‐281) and 13.7 pM (ICHB‐164), in rank‐ordered agreement of their KD values determined in vitro. The three reversal agents exhibited different neutralisation characteristics in vivo, governed primarily by their binding kinetics to JNJ‐9375. The model predicted a priori free JNJ‐9375 kinetics after dosing ICHB‐164 (JNJ‐67842125) and JNJ‐9375 under a different regimen.Conclusion and ImplicationsThe results enabled selection of JNJ‐67842125 as the reversal agent for JNJ‐9375.

The concentration-QTc (C-QTc) analysis is often applied in the first-in-human (FIH) study to demonstrate the absence of a QTc effect in support of a TQT waiver. However, a C-QTc analysis without properly designed sensitivity could fail to conclude the absence of a QTc effect at high concentrations, even though the compound is QTc negative. This is because the 90% confidence interval (CI) of the model-derived ∆∆QTc grows wider with increasing concentration, and the upper-bound could cross the 10-ms threshold, even though the slope is close to 0. So far, there is no simple math formula to calculate the sensitivity/specificity of a C-QTc analysis. A PK/QTc trial simulation scheme was applied to optimize the design features of a C-QTc trial in FIH studies by evaluating the study's sensitivity over a wide concentration range, circumventing the problem of not knowing the target concentration during FIH studies. It was also used to ensure that the specificity of the trial was well-controlled. Simulation showed that the study sensitivity can be quantitatively gauged by optimizing the dose range, the number of samples per subjects or subject number, and by sampling around Tmax, and at steady-state. The specificity of the trial can also be evaluated with this approach, and it is important to combine model-derived ∆∆QTc and slope estimate in the evaluation. The trial simulation approach helps maximize the probability of success of C-QTc analyses in FIH studies intended to support a TQT waiver.

Pharmacodynamics (PD) similarity is an important component to support the claim of similarity between two drugs or devices. This article investigates the trial design and statistical considerations in the equivalence test of PD endpoints. Using bone resorption marker CTX as a case study, the relationship between the PD readouts and drug potency was explored to evaluate the sensitivity of the PD endpoint and guide equivalence margin selection. For PD data that have high baseline variability, one conventional similarity assessment method was to apply baseline-normalization followed by the standard bioequivalence (BE) test (Lancet Haematol. 4:e350–61, 2017, Ann Rheum Dis. 2017). This study showcased the drawbacks of the conventional method for PD data that were close to inhibition saturation, as the baseline-normalization significantly skewed the distribution of the PD data toward non-log-normal. In such cases, the standard BE test can produce an inflated type I error. Alternatively, ANCOVA, when applied to the un-normalized PD data with the baseline as a covariate, produced a satisfactory type I error with sufficient power. Therefore, ANCOVA was recommended for equivalence test of PD markers that has a saturated inhibition profile and high variability at baseline. Moreover, the relationship between PD readouts and drug potency was used to explore the sensitivity of the PD endpoint and it could help justify the equivalence margins, since the standard 80% to 125% BE margin often does not apply to PD. Finally, a decision tree was proposed to help guide the design of the PD equivalence study in the choice of PD endpoints and statistical methods.

In pediatric drug development, large amounts of adult data are often available before the start of a pediatric study. It is believed that borrowing this information will improve the efficiency. However, when adult information is not sufficiently similar to that of pediatrics, incorporating adult data will introduce bias and consequently result in efficiency loss. A Bayesian alternative-namely, commensurate prior approach where the level of information borrowing is based on the concordance of adult and pediatric data-was investigated. Simulation results indicate that the commensurate prior approach, in general, provides a balanced and robust trade-off between bias and efficiency gain. The benefit of this approach was quantified in terms of sample size savings, and recommended sample sizes are provided.

AimCanagliflozin is an SGLT2 inhibitor approved for the treatment of type‐2 diabetes. A dynamic population pharmacokinetic–pharmacodynamic (PK/PD) model relating 24‐h canagliflozin exposure profiles to effects on glycosylated haemoglobin was developed to compare the efficacy of once‐daily and twice‐daily dosing.MethodsData from two clinical studies, one with once‐daily, and the other with twice‐daily dosing of canagliflozin as add‐on to metformin were used (n = 1347). An established population PK model was used to predict full 24‐h profiles from measured trough concentrations and/or baseline covariates. The dynamic PK/PD model incorporated an Emax relationship between 24‐h canagliflozin exposure and HbA1c‐lowering with baseline HbA1c affecting the efficacy.ResultsInternal and external model validation demonstrated that the model adequately predicted HbA1c‐lowering for canagliflozin once‐daily and twice‐daily dosing regimens. The differences in HbA1c reduction between the twice‐daily and daily mean profiles were minimal (at most 0.023% for 100 mg total daily dose [TDD] and 0.011% for 300 mg TDD, up to week 26, increasing with time and decreasing with TDD) and not considered clinically meaningful.ConclusionsSimulations using this model demonstrated the absence of clinically meaningful between‐regimen differences in efficacy, supported the regulatory approval of a canagliflozin‐metformin immediate release fixed‐dose combination tablet and alleviated the need for an additional clinical study.

The computational effort required to fit the pharmacodynamic (PD) part of a pharmacokinetic/pharmacodynamic (PK/PD) model can be considerable if the differential equations describing the model are solved numerically. This burden can be greatly reduced by applying the method of averaging (MAv) in the appropriate circumstances. The MAv gives an approximate solution, which is expected to be a good approximation when the PK profile is periodic (i.e. repeats its values in regular intervals) and the rate of change of the PD response is such that it is approximately constant over a single period of the PK profile. This paper explains the basis of the MAv by means of a simple mathematical derivation. The NONMEM ® implementation of the MAv using the abbreviated FORTRAN function FUNCA is described and explained. The application of the MAv is illustrated by means of an example involving changes in glycated hemoglobin (HbA1c%) following administration of canagliflozin, a selective sodium glucose co-transporter 2 inhibitor. The PK/PD model applied to these data is fitted with NONMEM ® using both the MAv and the standard method using a numerical differential equation solver (NDES). Both methods give virtually identical results but the NDES method takes almost 8 h to run both the estimation and covariance steps, whilst the MAv produces the same results in less than 30 s. An outline of the NONMEM ® control stream and the FORTRAN code for the FUNCA function is provided in the appendices.

Adaptive designs (AD) have received a great deal of attention in recent years because of the potential they offer to improve the efficiency of clinical drug development. In an increasingly challenging environment, characterized by escalating costs and decreasing likelihood of regulatory approval, sponsors and regulators alike have a keen interest in strategies to modernize drug development the use of AD is a key one among them.This chapter presents an overview of AD and their use in clinical drug development. It starts with some background and definitions, followed by sections on AD in the Learn and Confirm phases of clinical development. In later sections, the importance of trial simulations in the context of AD is discussed, followed by thoughts on the future of AD.

AbstractThis chapter describes modeling and simulation (M&S) applied to clinical drug development within a pharmaceutical company. M&S is a tool that shows us how a drug works and helps us design and interpret clinical trials. M&S also serves as a framework for what we learn in the precise language of mathematics.

Dose-regimen selection for confirmatory trials and characterization of dose-response relationship are arguably among the most important and difficult tasks in clinical drug development. Inadequate dose-regimen selection is believed to be one of the key drivers of the high attrition rate in Phase III. Nowadays, drug concentrations are routinely measured in patients in clinical studies throughout the drug development process. This drug exposure information is often used to explain some of the response variability. It could also be used to improve characterization of dose-response, and consequently result in a better dose-regimen selection. A simulation study was undertaken to assess the potential value of dose-response characterization methods that utilize exposure data relative to methods that only require dose and response data.

Inadequate selection of the dose to bring forward in confirmatory trials has been identified as one of the key drivers of the decreasing success rates observed in drug development programs across the pharmaceutical industry. In recognition of this problem, the Pharmaceutical Research and Manufacturers of America (PhRMA), formed a working group to evaluate and develop alternative approaches to dose finding, including adaptive dose-ranging designs. This paper summarizes the work of the group, including the results and conclusions of a comprehensive simulation study, and puts forward recommendations on how to improve dose ranging in clinical development, including, but not limited to, the use of adaptive dose-ranging methods.

An open‐label pharmacokinetic and pharmacodynamic study of zoledronic acid (Zometaθ) was performed in 19 cancer patients with bone metastases and known, varying levels of renal function. Patients were stratified according to creatinine clearance (CL cr ) into different groups of normal (CL cr > 80 mL/min), mildly (CL cr = 50–80 mL/min), or moderately/severely impaired (CL cr = 10–50 mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were administered at 1‐month intervals between doses. Plasma concentrations and amounts excreted in urine were determined in all subjects, and 4 patients were administered 14 C‐labeled zoledronic acid to assess excretion and distribution of drug in whole blood. In general, the drug was well tolerated by the patients. Mean area under the plasma concentration versus time curve and mean concentration immediately after cessation of drug infusion were lower, and mean amounts excreted in urine over 24 hours from start of infusion were higher in normal subjects than in those with impaired renal function (36% vs. 28% of excreted dose), although the differences were not significant. Furthermore, with repeated doses, there was no evidence of drug accumulation in plasma or changes in drug exposure in any of the groups, nor was there any evidence of changes in renal function status. Serum levels of markers of bone resorption (serum C‐telopeptide and N‐telopeptide) were noticeably reduced after each dose of zoledronic acid across all three renal groups. It was concluded that in patients with mildly to moderately reduced renal function, dosage adjustment of zoledronic acid is likely not necessary.

BACKGROUND:Everolimus is a macrolide immunosuppressant intended for acute rejection prophylaxis after kidney transplantation.METHODS:A total of 5260 blood samples were collected in the context of two randomized, double-blind, multicenter efficacy trials in 673 patients over a 6-month period after kidney transplantation. The data were evaluated in a nonlinear mixed-effects model. The influence of demographic characteristics (age, weight, sex, and ethnicity) and of comedications on everolimus exposure was explored.RESULTS:For a reference 44-year-old, 71-kg Caucasian kidney allograft recipient receiving everolimus as part of a cyclosporine (INN, ciclosporin)-prednisone immunosuppressive regimen, the absorption rate constant was 6.07 h(-1) (standard error [SE], 0.70 h(-1)), the apparent clearance was 8.8 L/h (SE, 0.2 L/h), and the apparent central distribution volume was 110 L (SE, 5 L). There were no clinically relevant influences of age, weight, or sex on clearance. No significant difference in clearance was detected for Asian patients, whereas black patients had an average clearance that was 20% higher than that of nonblack patients. Patients concomitantly receiving erythromycin or azithromycin had an average 19% lower clearance. One patient receiving itraconazole had a 74% reduction in clearance. After we accounted for covariates, the remaining interindividual variability in clearance was 27% and the variability for distribution volume was 36%. The combined intraindividual and assay/measurement residual error in everolimus blood concentrations was 31%.CONCLUSIONS:Dose adjustment of everolimus on the basis of weight does not appear necessary. Black patients may need a higher dose to achieve exposure that is similar to that of nonblack patients. Concomitant administration of potent inhibitors of the cytochrome P450 isozyme CYP3A may reduce everolimus clearance and increase its blood concentrations.

1. BACKGROUND In the spring of 2005, the Pharmaceutical Innovation Steering Committee (PISC) of PhRMA formed several working groups to look into different drivers of the decreasing success rates observed in drug development programs across the pharmaceutical industry, identified in a previous survey conducted by a consulting group. Among those was the Adaptive Dose-Ranging Designs (initially called Rolling Dose Studies) working group. The objectives of this group are to develop new and evaluate existing adaptive dose- ranging methods, and to produce policy recommendations for regulatory agencies on their use in clinical drug development. This paper summarizes the work of the group, including the results and conclusions of a comprehensive simulation study, and puts forward recommendations on how to improve dose ranging in clinical development, including, but not limited to, the use of adaptive dose-ranging methods.