Population pharmacokinetics of LXE408 in healthy volunteers and dose predictions for adults and pediatric patients with visceral leishmaniasis
Ivan Demin, Giulia Lestini
Pharmacometrics, Analytics GDD, Novartis
Objectives: To describe the population pharmacokinetics of LXE408, a novel kinetoplastid proteasome inhibitor, after oral administration in healthy volunteers in a first in human (FIH) study. To predict pharmacologically active doses for phase 2 study in adult patients with visceral leishmaniasis (VL). To predict pediatric doses in patients ≥10 kg that match exposure of adults at the dose selected for phase 2 study in patients with VL (NCT05593666).
Methods: The population PK (popPK) model was built using the nonlinear mixed-effects approach and was implemented in MonolixSuite 2021R2. The structural model was parameterized in terms of apparent clearance (CL/F), apparent volume of distribution (V/F), zero-order absorption duration (Tk0), lag time before absorption (Tlag) and relative bioavailability (F). Between-subject variability was introduced on all structural parameters. Residual unexplained variability was modeled using a proportional error model.
The established popPK model was used for PK simulations of candidate doses for the phase 2 study. Between-subject variability was inflated by 30% to reflect higher expected variability in patients. Based on preclinical PKPD experiments, it was concluded that having free drug concentrations above the in-vitro EC50 value for 70% of time over the dosing interval correlated with efficacy in preclinical models of VL. This PKPD target was used for simulations to determine the pharmacologically active dose. Individual body weights of Asian VL patients from field study in India [1] was used for these simulations.
Once the dose for adult VL patients was selected, pediatric simulations were performed assuming allometric scaling of PK parameters with the aim to identify pediatric doses that result in similar exposure as the adult target dose.
Results: The final popPK model was a one-compartment disposition model with zero-order absorption and linear elimination. The observed dose under-proportional PK was captured in the model as dose effect on relative bioavailability F. Population parameter estimates were CL/F=5.4 L/h, V/F=140 L, Tk0=1 1/h, Tlag=0.28h. Body weight was introduced in the model as a covariate with fixed allometric coefficients of 0.75 for CL/F and 1 for V/F. The estimated dose effect on F was -0.22 on the log scale, indicating a decreasing bioavailability with increasing dose.
The mean body weight of adult Asian VL patients used for these simulations was 47 kg. PK simulations estimated that doses in the range 65-100 mg once daily (q.d.) would reach the preclinical PKPD target in 90-95% of adult VL patients. Nevertheless, since doses up to 600 mg q.d. for 10 days were well tolerated in healthy volunteers in the FIH study, a dose of 300 mg q.d. was selected for phase 2 study in adult VL patients to maximize potential treatment benefits.
Several dose adjustment schemes with fixed doses per weight band were considered for pediatric patients. The following dose adjustment scheme allowed an acceptable match of the adult target exposure:
- 10 to <20 kg: 75 mg
- 20 to <30 kg: 150 mg
- ≥30 kg: 300 mg
It should be noted that these preliminary simulations are exploratory in nature. Pediatric dose predictions will be iteratively updated with incoming data, such as PK data from adult VL patients and adolescent PK data, etc.
Conclusions: LXE408 concentration time profiles were adequately described by a one-compartment disposition model with zero-order absorption and linear elimination. Body weight was introduced in the model as a covariate with fixed allometric coefficients of 0.75 for CL/F and 1 for V/F. PK simulations estimated that doses in the range 65-100 mg q.d. could be efficacious in adult VL patients. The decision to test a higher dose of 300 mg q.d. was based on the totality of safety data observed in the FIH study, with the aim to maximize efficacy. Using real world data on weight distribution of VL patients helped refine dose predictions, including for pediatric patients. The initial pediatric simulations were performed with the aim to inform formulation development for pediatric dose strengths.
Acknowledgments: We would like to thank Fabiana Alves and DNDi for providing individual body weights of patients from field study in India published in [1].
References:
[1] Goyal V, Mahajan R, Pandey K, et al. Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India. PLoS Negl Trop Dis. 2018 Oct 22;12(10)
