Population pharmacokinetics of riociguat in a pediatric population (aged ≥ 6 years) with pulmonary arterial hypertension.

BACKGROUND: The PATENT-CHILD study investigated riociguat in children aged ≥ 6 to <18 years with pulmonary arterial hypertension (PAH) treated with tablets or an oral pediatric suspension based on bodyweight-adjusted dosing of up to 2.5 mg three times daily. PATENT-CHILD demonstrated an acceptable riociguat safety profile and individual plasma concentrations in pediatric patients were consistent with those in adult patients. METHODS: Using the data set from PATENT-CHILD and building on existing population pharmacokinetic (PK) models for riociguat and its major metabolite (M1) in adults with PAH, a coupled riociguat-M1 PK model was developed. The final model developed incorporated a one-compartment model for riociguat, coupled to a one-compartment model for M1, allowing for presystemic formation of M1. It included allometric scaling exponents for bodyweight. RESULTS: Apparent clearance of riociguat was similar in children and adult patients with PAH (median [interquartile range] 2.20 [1.75-3.44] and 2.08 L/h [1.55-2.97]). Factors contributing to lower PK exposure were lower riociguat maintenance dose in PATENT-CHILD, and a higher riociguat clearance in some adolescent patients, compared with adult patients. No effects of formulation, sex, or age on riociguat PK were observed. An exploratory PK/pharmacodynamics analysis found the increase in 6-min walking distance in pediatric patients treated with riociguat was not related to riociguat PK. CONCLUSIONS: Body size is the main determinant of PK in growing children, and the model supports clinical data that, for children weighing < 50 kg, a bodyweight-adjusted dose of riociguat should be used to achieve a similar exposure to that observed in adults with PAH.

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake.

AIM: Regorafenib is an oral multikinase inhibitor with clinical efficacy in a range of advanced solid tumours. A population pharmacokinetic (PK) model was developed to evaluate the variability of the PK of regorafenib and its pharmacologically active metabolites M-2 and M-5 in solid tumours. METHODS: The model was initially developed using densely sampled phase 1 data and information on food intake to incorporate enterohepatic circulation (EHC) that was identified to considerably contribute to the PK of regorafenib. This was then applied to sparsely sampled data from four phase 3 studies in patients with advanced solid tumours. The need for exact food intake data to estimate individual drug exposure was evaluated. RESULTS: By incorporating EHC, the model adequately described the PK profiles of regorafenib, M-2 and M-5 after single and multiple doses in patients from phase 1 studies. Individual exposure in phase 3 studies was adequately described based on assumptions on the time and frequency of food intake, although exact food intake data are recommended to improve the estimation. Covariate analysis identified sex and body mass index (BMI) as impacting exposure to regorafenib, and sex as strongly impacting exposure to M-2 and M-5 (also influenced by the BMI effect on parent regorafenib in the joint model developed); however, these factors accounted for a small portion of the overall variability in exposure. CONCLUSIONS: The adequate description of regorafenib PK after multiple dosing requires the incorporation of EHC. Neither single nor combined covariates predicted exposures that would warrant a priori regorafenib dose adjustment.

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach.

The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of 'typical' popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Non-linear PK was excluded from the datasets and a 2-compartment model was applied to describe mAb disposition. Typical human popPK estimates compared well with data from comparator mAbs with linear PK in the clinic. Outliers with higher than typical clearance were found to have non-specific interactions in an affinity-capture self-interaction nanoparticle spectroscopy assay, offering a potential tool to screen out these mAbs at an early stage. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

Exposure-response relationship of regorafenib efficacy in patients with hepatocellular carcinoma.

PURPOSE: To explore the relationship between regorafenib exposure and efficacy in patients with hepatocellular carcinoma (HCC) who had disease progression during sorafenib treatment (RESORCE). METHODS: Exposure-response (ER) analyses for regorafenib were performed using data from a phase 3, randomized, placebo-controlled trial (RESORCE). Patients received 160mg regorafenib or placebo once daily (3weeks on/1week off in a 4-week cycle) with best supportive care until disease progression, death, or unacceptable toxicity. Kaplan-Meier analyses for overall survival (OS) and time-to-progression (TTP) were performed in which regorafenib-treated patients were grouped into four categories according to their estimated average exposure over 4weeks in cycle 1. While this analysis primarily focused on efficacy, a potential correlation between exposure and treatment-emergent adverse events (TEAEs) was also evaluated. If any differences were observed between Kaplan-Meier plots, the ER analysis continued with a multivariate Cox regression analysis to evaluate the correlation between exposure quartile categories and the efficacy and safety parameters while taking into consideration the effect of the predefined clinically relevant demographic and baseline covariates. The functional form of the ER relationship within the regorafenib treatment group was subsequently evaluated. RESULTS: Based on visual assessment of the Kaplan-Meier plots, no meaningful relationship between the exposure categories and TEAEs were observed, although median OS and TTP tended to be longer in the higher exposure categories. Further ER analyses, which considered the effects of predefined covariates and the different shapes of the ER relationship, focused on efficacy. The baseline risk factors Eastern Cooperative Oncology Group (ECOG) performance status ≥1, alpha-fetoprotein levels ≥400ng/ml, and aspartate transaminase or alanine transaminase levels >3×upper limit of normal were significantly associated with OS (P<0.01) and age was associated with TTP. A statistically significant difference was found for OS and TTP between patients receiving regorafenib compared with those receiving placebo in the multivariate ER analysis (P<0.01) in favor of regorafenib. However, within the group of regorafenib-treated patients, the effect of regorafenib exposure on efficacy, either by estimating four effect sizes for each quartile, or by including a continuous linear or nonlinear relationship between individual exposure and efficacy, was not significant (P>0.01) and relatively flat. This suggests that increasing regorafenib exposure would not result in a meaningful increase in OS or TTP. CONCLUSION: After considering the baseline risk factors: ECOG performance status, alpha-fetoprotein levels, and hepatic function for OS and age for TTP, the ER analysis in regorafenib-treated patients showed similar efficacy over the entire predicted exposure range in RESORCE. This supports the selected regorafenib dose of 160mg once daily (3weeks on/1week off in a 4-week cycle) in patients with intermediate or advanced HCC who have experienced disease progression on sorafenib.