Moxifloxacin is a widely used fluoroquinolone for the treatment of complicated intra‐abdominal infections. We applied physiologically‐based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) modeling to support dose selection in pediatric patients. We scaled an existing adult PBPK model to children based on prior physiological knowledge. The resulting model proposed an age‐dependent dosing regimen that was tested in a phase I study. Refined doses were then tested in a phase III study. A popPK analysis of all clinical pediatric data confirmed the PBPK predictions, including the proposed dosing schedule in children, and supported pharmacokinetics‐related safety/efficacy questions. The pediatric PBPK model adequately predicted the doses necessary to achieve antimicrobial efficacy while maintaining safety in the phase I and III pediatric studies. Altogether, this study retroactively demonstrated the robustness and utility of modeling to support dose finding and confirmation in pediatric drug development for moxifloxacin.

We report population pharmacokinetic (popPK) and exposure-response (E-R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan.Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids.Methods: A popPK model was developed using data from Phase 1 and 2 studies (including ASTEROID 1 and 2). The relationship between vilaprisan exposure (steadystate AUC) and IA after oral administration of 0.5, 1, 2 or 4 mg/day over 3 months was analysed in ASTEROID 1 using logistic regression and qualified in ASTEROID 2 by comparing simulated and observed probability for IA after 2 mg/day. The exposure-E2 relationship was analysed visually.Results: Vilaprisan clearance was 22.7% lower in obese vs non-obese patients. The E-R relationship for IA in ASTEROID 1 was steep and consistent with ASTEROID 2, with a maximum probability (P max ) of 59% (95% CI: 49-68%). The exposure at which 50% of P max is obtained was 36.9 μg*h/L (95% CI: 27.7-48.7 μg*h/L). Simulations showed that 36% of the patients will be below 90% of P max for IA after 1 mg/day compared to 2% after 2 mg/day. E2 levels tended to decrease with increasing exposure. While E2 levels remained largely within the physiologic follicular phase range, the clinical relevance of this decrease will be evaluated in long-term studies.Conclusions: A 2 mg/day dose was selected for Phase 3 as E-R analyses show this dose results in a close to maximum probability for IA, without any safety concerns noted.

Background Vericiguat, a stimulator of soluble guanylate cyclase, has been developed as a first-in-class therapy for worsening chronic heart failure in adults with left ventricular ejection fraction < 45%. Objective The objective of this article was to characterize the pharmacokinetics and pharmacokinetic variability of vericiguat combined with guideline-directed medical therapy (standard of care), and identify exposure-response relationships for safety (hemodynamics) and pharmacodynamic markers of efficacy (N-terminal pro-B-type natriuretic peptide concentration [NT-proBNP]) in patients with heart failure and left ventricular ejection fraction < 45% in the SOCRATES-REDUCED study (NCT01951625). Methods Vericiguat and NT-proBNP plasma concentrations in 454 and 432 patients in SOCRATES-REDUCED, respectively, were analyzed using nonlinear mixed-effects modeling. Results Vericiguat pharmacokinetics were well described by a one-compartment model with apparent clearance, apparent volume of distribution, and absorption rate constant. Age, bodyweight, plasma bilirubin, and creatinine clearance were identified as significant covariates on apparent clearance; sex and bodyweight on apparent volume of distribution; and bodyweight and plasma albumin level on absorption rate constant. Pharmacokinetic/pharmacodynamic analysis showed initial minor and transient effects of vericiguat on blood pressure with low clinical impact. There were no changes in heart rate following initial or repeated vericiguat administration. An exposure-dependent and time-dependent turnover pharmacokinetic/pharmacodynamic model for NT-proBNP described production and elimination rates and an demonstrated exposure-dependent reduction in [NT-proBNP] by vericiguat plus standard of care compared with placebo plus standard of care. This effect was dependent on baseline [NT-proBNP]. Conclusions Vericiguat has predictable pharmacokinetics, with no long-term effects on blood pressure in patients with heart failure and left ventricular ejection fraction < 45%. A pharmacokinetic/pharmacodynamic model described a vericiguat exposure-dependent reduction of NT-proBNP. Clinical Trial Identifier NCT01951625.

Vilaprisan is a highly potent selective progesterone receptor modulator in development for the treatment of symptomatic uterine fibroids and endometriosis. Its pharmacokinetics are characterized by rapid absorption, almost complete bioavailability, and dose-proportional exposure. The intrinsic factors of age, bodyweight, and race have no clinically relevant effect on the pharmacokinetics and pharmacodynamics of vilaprisan and do not warrant a dose adjustment. Similarly, vilaprisan can be used in patients with mild or moderate renal or hepatic impairment without dose adjustment, but its use is not recommended in patients with severe organ impairment. Vilaprisan has no perpetrator potential on cytochrome P450 (CYP) enzymes or transporters and therefore restrictions in the concomitant use of their substrates are not required. Nonetheless, because it is a sensitive CYP3A4 substrate itself, concomitant use of vilaprisan with strong CYP3A inhibitors or inducers is not recommended. However, there is no risk for QTc prolongation when vilaprisan and a strong CYP3A inhibitor are administered concomitantly, as indicated by a vilaprisan concentration-QTc response analysis across all studies with triplicate electrocardiogram measurements. Furthermore, due to its mode of action, vilaprisan is also not recommended to be used together with progestin-containing oral contraceptives. Vilaprisan shows a steep exposure-response relationship for inducing amenorrhea in patients with uterine fibroids experiencing heavy menstrual bleeding. Based on simulations, a dose of 2 mg/day is expected to induce a maximum bleeding reduction and was thus selected for phase III.

Introduction Vericiguat is a soluble guanylate cyclase stimulator developed for the treatment of symptomatic chronic heart failure (HF) in patients with ejection fraction less than 45% who had a previous decompensation event. A dedicated, randomised, Phase Ib, QT study of vericiguat (NCT03504982) in 74 adult patients with stable coronary artery disease demonstrated no clinically significant prolongation of the time-matched, placebo-adjusted change from baseline in the Fridericia-corrected QT interval (QTcF) after vericiguat 10 mg once daily at steady state. Purpose We conducted a concentration–QTc (C-QTc) modelling analysis, on data from the QT study, to investigate the potential effect of vericiguat on QTcF and define the vericiguat plasma concentration window within which a relevant prolongation in QTcF can be excluded. Methods In the QT study, the effect of vericiguat once daily (2.5 mg titrated to 5 mg and then to 10 mg [treatments A, B, C] over 42±9 days) on the QT interval was investigated. The positive control was a single dose of moxifloxacin 400 mg (treatment D) on Day 8 or Day 50 (7 days before the first vericiguat dose or 7 days after the last vericiguat dose), depending on the treatment sequence (Figure 1). Baseline electrocardiogram assessments were performed 24 h before the start of treatment (“baseline”) and at follow-up (“back-up baseline”; Figure 1). Time-matched, baseline- and placebo-adjusted QTcF (ΔΔQTc) mean values and 90% confidence intervals (CIs) were calculated. Two analytical approaches were used to calculate ΔΔQTc. The first one (“single baseline ΔΔQTc” approach) was data-driven, where ΔΔQTc was adjusted with placebo- and either “baseline” or “back-up baseline”. The second one (“modelled baseline ΔΔQTc”) accounted for individual baseline and placebo effects, such as diurnal time course, used linear mixed effects and integrated all individual baseline and placebo data. Calculated ΔΔQTc values were then related to observed vericiguat concentrations in the C-QTc modelling step, performed with linear mixed effects implemented in R (R, the R Foundation for Statistical Computing, version 3.2.5). Results The C-QTc modelling of ΔΔQTc calculated with the “single baseline ΔΔQTc” approach indicated a positive, but non-significant, slope (Figure 2A). The “modelled baseline ΔΔQTc” approach indicated a positive and statistically significant slope (Figure 2B). In both cases, the upper limits of the 90% CI were below the threshold of clinical relevance of 10 ms within the investigated exposure range (up to 745 μg/l). Conclusion Based on the presented analysis, a clinically meaningful QT prolongation was robustly excluded within the plasma concentration range associated with the recommended target dose of vericiguat 10 mg. The C-QTc analysis supports the conclusion of the primary study statistical analysis that administration of vericiguat between 2.5 and 10 mg is not associated with a clinically meaningful QTc prolongation. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding was provided by Bayer AG, Berlin, Germany and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Figure 1 Figure 2