A nonlinear mixed effects IVIVC model for multi-release drug delivery systems

The purpose of this analysis was the development of an IVIVC model, which involves a convolution step as described by O'Hara et al. and to describe a dual-release system: a controlled release formulation, which contains an initial immediate release element. Four formulations of Galantamine((R)) were used to test this modelling technique and a level A IVIVC, which meets the FDA criteria for internal and external validation, was successfully developed

Population pharmacokinetics (popPK) to evaluate the effect of intrinsic and extrinsic factors on regorafenib (REG) exposure in REG studies including patients with hepatocellular carcinoma (HCC).

320 Background: REG is approved for refractory metastatic colorectal cancer (CRC) and gastrointestinal stromal tumors (GIST). In the phase 3 RESORCE trial (N = 573), REG (160 mg QD, 3 weeks on/1 week off) significantly (P &lt; 0.001) improved overall survival (OS) vs placebo in HCC patients who progressed on sorafenib (HR 0.63; 95% CI 0.50‒0.79). We evaluated REG PK in RESORCE using a popPK model and the influence of intrinsic and extrinsic factors (covariates) on REG PK. Methods: The average concentrations of REG and its pharmacologically active metabolites (M-2, M-5) were estimated based on sparse PK sampling in cycles 1–2. A covariate analysis was conducted using exposure and covariate data in 16 clinical REG trials in CRC, GIST, and HCC (1337 subjects) using a graphical and generalized additive modeling (GAM) approach. Results: eGFR, total plasma protein, hematocrit, total bilirubin, AST, ALP, and Asians vs non-Asians did not significantly (p &gt; 0.05) influence exposure, whereas covariates significantly (p &lt; 0.05) influencing exposure in 16 studies including RESORCE were: being a healthy volunteer vs a patient, sex, age, hemoglobin at baseline, plasma albumin at baseline, BMI, and body weight. The identified covariate effects were considered small compared with observed overall variability in exposure. Visual comparison of the exposure estimates in RESORCE showed these were comparable to those in phase 3 studies in CRC and GIST. Exposure in Asians was comparable to that in the rest of the world (ROW) and there was no apparent difference in exposure between Japanese, Chinese, and ROW and between patients with mild/moderate hepatic impairment vs normal hepatic function. Only small numerical differences in exposure across different age categories were observed, with a tendency towards higher exposure in patients ≥ 65 years of age. Conclusions: The RESORCE data confirm previous observations that the identified covariates that significantly (P &lt; 0.05) correlated with exposure only describe a small fraction ( &lt; 10%) of the overall variability in exposure and, thus, are not expected to have a clinically relevant impact on REG exposure. Clinical trial information: NCT01774344. </jats:p

A time scaling approach to develop an in vitro-in vivo correlation (IVIVC) model using a convolution-based technique

In vitro-in vivo correlation (IVIVC) models prove very useful during drug formulation development, the setting of dissolution specifications and bio-waiver applications following post approval changes. A convolution-based population approach for developing an IVIVC has recently been proposed as an alternative to traditional deconvolution based methods, which pose some statistical concerns. Our aim in this study was to use a time-scaling approach using a convolution-based technique to successfully develop an IVIVC model for a drug with quite different in vitro and in vivo time scales. The in vitro and the in vivo data were longitudinal in nature with considerable between subject variation in the in vivo data. The model was successfully developed and fitted to the data using the NONMEM package. Model utility was assessed by comparing model-predicted plasma concentration-time profiles with the observed in vivo profiles. This comparison met validation criteria for both internal and external predictability as set out by the regulatory authorities. This study demonstrates that a time-scaling approach may prove useful when attempting to develop an IVIVC for data with the aforementioned properties. It also demonstrates that the convolution-based population approach is quite versatile and that it is capable of producing an IVIVC model with a big difference between the in vitro and in vivo time scales

Predicted heart rate effect of inhaled PF-00610355, a long acting β-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease

AIM: To assess the cardiovascular effects of a new inhaled long-acting β-adrenoceptor agonist PF-00610355 in COPD patients. METHODS: Thirteen thousand and sixty-two heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma and COPD patients were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, patient status, demographics and concomitant medication was evaluated using non-linear mixed-effects models. The median heart rate increase in COPD patients for doses of PF-00610355 up to 280 μg once daily was simulated with the final pharmacokinetic/pharmacodynamic (PKPD) model. RESULTS: An E(max) model accounting for delayed on-and off-set of the PF-00610355-induced change in heart rate was developed. The predicted potency in COPD patients was three-fold lower compared with healthy volunteers, while no difference in maximum drug effect was identified. Simulations suggested a maximum placebo-corrected increase of 2.7 (0.90–4.82) beats min(−1) in COPD patients for a PF-00610355 dose of 280 μg once daily, with 19% subjects experiencing a heart rate increase of more than 20 beats min(−1) compared with 8% in the placebo group. CONCLUSIONS: This PKPD analysis supports the clinical observation that no relevant effects of PF-00610355 on heart rate in COPD patients should be expected for doses up to 280 μg once daily