Alan Faraj (1), Rob van Wijk (1), Yasunori Aoki (1), Linda Neuman (2), Shraddha Desai (2), Grant E Blouse (2), Tom Knudsen (2), Ulrika S.H. Simonsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Catalyst Biosciences, South San Francisco, CA, USA
Objectives: Marzeptacog alfa (activated) (MarzAA), a novel engineered recombinant activated Factor VII is in clinical development for subcutaneous (SC) administration for episodic treatment of bleeding in individuals with hemophilia A (HA) or B (HB) with inhibitors and other inherited bleeding disorders. This work aimed to support the paediatric Phase 3 trial dose selection for SC MarzAA in paediatrics with HA/HB with inhibitors through simulations investigating:
i. Exposure-matching strategy to support dose selection
ii. Probability of trial success (PTS)
iii. Trial design power to estimate clearance (CL) and volume of distribution (V)
Methods: A previously developed population pharmacokinetic (popPK) model for MarzAA in adults including allometric scaling was used to simulate pharmacokinetic (PK) profiles following varying single SC doses in age groups (0.5, 1, 2, 4 ,6, 11 years, n=1000 per group). The 95% prediction interval (PI) of AUC0-24h and Cmax(0-24h) per age group and dose level were compared to the adult PIs after a single 60 µg/kg SC dose. Given that MarzAA PK exhibits absorption-limited elimination and that the rate of absorption in children has been shown in the literature [1, 2] to be higher relative to adults for some therapeutic proteins, a hypothetical increase (2x) of rate of absorption following single SC doses of 60, 90 and 120 µg/kg were simulated for each of the different age groups. PTS was evaluated by simulating PK profiles for 24 new paediatric subjects between 0 and 11 years of age in 1000 clinical trials following a single SC dose of 60 µg/kg. Each subjects AUC0-24h and Cmax(0-24h) was compared with the adult PI (AUC0-24h; 196-1611 h*ng/mL, Cmax(0-24h); 12-93 ng/mL) resulting from the same dose. A given trial was considered successful if >80% of the subjects were predicted to be within the adult PI for AUC0-24h or Cmax(0-24h). Lastly, the study power to estimate clearance (CL) and volume of distribution (V) with sufficient certainty for a Phase 3 trial in paediatrics given a stand-alone analysis were performed using stochastic simulations and estimations (SSE) [3].
Results: The simulated AUC0-24h PI remained within the matching adult PI for the lowest dose of 60 µg/kg for all age groups except the 11 year and 6 year age groups, in which the 97.5% percentile was slightly above the matching PI. For Cmax(0-24h), the 60 µg/kg SC dose produced similar PI as the matching target whereas the upper boundary of the PI of the higher doses were above the adult 97.5th percentile. Assuming a doubling of the absorption rate constant in the children compared to the adults favorably shifted the 2.5th percentile in all age groups for the 60 µg/kg dose to better match the adult PI for both AUC0-24h and Cmax(0-24h). The upper bound of the 95% PI of Cmax(0-24h) was above the matching range for all three doses on which increase in absorption rate were studied. The PTS following a single dose of 60 µg/kg in all age groups were 93% and 91% based on AUC0-24h and Cmax(0-24h), respectively. The power for estimating CL and V with sufficient certainty for a proposed design (n=24 children) was 74% and 6%, respectively, indicating that a stand-alone analysis of the paediatric data might be of limited value. Doubling the sample size did not substantially alter this result.
Conclusions: This work supports using 60 μg/kg SC MarzAA in a Phase 3 paediatric trial in HA/HB with inhibitors. The results suggest that the Phase 3 paediatric PK data should be analyzed as a pooled analysis with earlier adult data or using priors.
References:
[1] Robbie RJ, Zhao L, Mondick J, Losonsky G, Roskos LK. 2012. Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody in adults and children. Antimicr. Agents Chemoth. 56(9): 4927-4936
[2] Temrikar ZH, Suryawanshi S, Meibohm B. 2020. Pharmacokinetics and clinical pharmacology of monoclonal antibodies in paediatric patients. Pediatr. Drugs. 22: 199-216.
[3] Wang Y, Jadhav PR, Lala M, Gobburu JV. 2012. Clarification on precision criteria to derive sample size when designing paediatric pharmacokinetic studies. J. Clin. Pharmacol. 52: 1601-1606
Reference: PAGE 29 (2021) Abstr 9866 [www.page-meeting.org/?abstract=9866]
Poster: Drug/Disease Modelling - Paediatrics