Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3.

Background: Recombinant von Willebrand factor (rVWF, vonicog alfa, Vonvendi/Veyvondi, Takeda Pharmaceuticals USA, Lexington, MA) and several plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrates are available for treating bleeding episodes in patients with von Willebrand disease (VWD). Purpose: To develop population pharmacokinetic (PK)/pharmacodynamic (PD) models that describe VWF:ristocetin cofactor (VWF:RCo) activity and its relationship with FVIII activity (FVIII:C) over time following intravenous administration of either rVWF or a pdVWF/FVIII concentrate (VWF:RCo/FVIII:C 2.4:1) in patients with VWD; to use the final PK/PD models for an in silico comparison of rVWF and pdVWF/FVIII. Methods: The population PK model for rVWF was based on data from four clinical studies in which rVWF was administered to adult patients with VWD type 1, 2 or 3 (phase 1: NCT00816660; phase 3: NCT01410227 and NCT02283268) or severe hemophilia A (phase 1: EudraCT 2011-004314-42). The PK and PK/PD models for pdVWF/FVIII were based on data from the phase 1 study (NCT00816660) in patients with type 3 VWD who received either rVWF plus recombinant FVIII (rFVIII, octocog alfa, ADVATE®, Takeda Pharmaceuticals USA, Lexington, MA, USA) or pdVWF/FVIII. Results: There was a marked difference in clearance following rVWF administration compared with pdVWF/FVIII in type 3 VWD, leading to a ~1.75 longer mean residence time (ie, persistence of VWF:RCo activity in the body) and half-life for rVWF versus pdVWF/FVIII. Simulations showed that following repeated administration of rVWF (50 IU/kg), a FVIII:C activity of >40 IU/dL can be maintained for the full 72 h dosing interval. Conclusion: The slower elimination of VWF:RCo following rVWF administration results in a prolonged effect on FVIII turnover compared with pdVWF/FVIII administration.

Conditional distribution modeling as an alternative method for covariates simulation: Comparison with joint multivariate normal and bootstrap techniques.

Clinical trial simulation (CTS) is a valuable tool in drug development. To obtain realistic scenarios, the subjects included in the CTS must be representative of the target population. Common ways of generating virtual subjects are based upon bootstrap (BS) procedures or multivariate normal distributions (MVNDs). Here, we investigated the performance of an alternative method based on conditional distributions (CDs). Covariate data from a hypertension drug development program were used. The methods were evaluated based on the original data set (internal evaluation) and on their ability to reproduce an older, unobserved population (extrapolation). Similar results were obtained in the internal evaluation for summary statistics, yet BS was able to preserve the correlation structure of the empirical distribution, which was not adequately reproduced by MVND; CD was in between BS and MVND. BS does not allow to extrapolate to an unobserved population. When the data set used to inform the extrapolation was well approximated by an MVND, the results from CD and MVND were comparable. However, improved extrapolation performance was observed for CD when deviations from normality assumptions occurred. If CTS is used to simulate within the observed distribution, BS is the preferred method. When extrapolating to new populations, a parametric method like CD/MVND is needed. In case the empirical multivariate distribution is characterized by linearly related covariates and unimodal marginal distributions, MVND can be used because of the simpler statistical framework and well-established use; however, if uncertainty about the MVND assumptions exists, CD will increase the confidence in the simulations compared to MVND.

Translating QT interval prolongation from conscious dogs to humans.

AIM: In spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. METHODS: Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between -0.98 ms µM-1 and 6.1 ms µM-1 in dogs and -10 ms µM-1 and 90 ms µM-1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species. RESULTS: For compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x; R2  = 0.989). These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs. CONCLUSIONS: Together with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans.