Ivan Demin (1), Jay Prakash Jain (2), Guoqin Su (3), Cornelis Winnips (1)
(1) Novartis Pharma AG, Switzerland, (2) Novartis Institute for Tropical Diseases (USA), (3) Novartis Pharmaceuticals
Objectives: Malaria is one of the most important infectious diseases that potentially threatens about 3.2 billion people, almost half of the world’s population. Despite increasing international efforts for malaria control, in 2015, there were 214 million cases worldwide of malaria and 438 000 deaths according to the latest World Health Organization estimates.
KAF156 (ganaplacide) belongs to a novel class of antimalarial, imidazolopiperazines, and is active against a broad range of Plasmodium species, including drug-resistant parasites. The compound is cidal against both blood and liver stages of the parasite and demonstrated efficacy in a proof of concept trial.
In contrast to the conventional lumefantrine formulation, lumefantrine solid dispersion formulation (LUM-SDF) has an improved absorption profile and less food effect, leading to exposure that allows for a once-daily regimen.
KAF156A2202 (ClinicalTrials.gov Identifier: NCT03167242) is a Phase 2b dose/regimen finding study of a combination of two anti-malarial compounds KAF156 and LUM-SDF. The treatment is given once daily for 1, 2 and 3-days to adults and children with uncomplicated plasmodium falciparum malaria. In total, six different treatment arms plus Coartem arm were tested. The study consists of three parts: PK run-in part (PK drug-drug interaction), dose-regimen finding part in adolescents and adults 12+ years old, and dose-regimen finding part in children 2-11 years old. PK run-in part and dose-regimen finding part in adolescents and adults 12+ years old have been completed and showed high cure rates in all treatment arms with a slightly lower response in single day arms.
The purpose of this analysis was to describe the dose-exposure-response relationship of KAF156/LUM-SDF using data from adult and adolescent patients and to support dose selection for pediatric patients aged 2-11 years old.
Methods: First, population PK models were built separately for KAF156 and LUM-SDF using Monolix 2018R1 software, based on rich and semi-rich PK concentration-time data from 349 malaria patients. Then, model-based day 7 concentrations were simulated and used for the exposure-response modeling, which was performed in R-3.4.3. The exposure-response relationship was described using a logistic regression model relating day 7 concentrations (Cday7) of both compounds to the probability of PCR-adjusted adequate clinical and parasitological response on day 28 (ACPR28). In addition, covariates, such as baseline parasitemia, age, etc., were evaluated.
The established dose-exposure-response model was used to simulate different scenarios for children 2-11 years old to support dose-regimen selection. R-3.4.3 and mlxR library version 3.3.0 were used to perform simulations.
Results: KAF156 PK was described by a two-compartment disposition model with first-order absorption and first-order elimination. The effect of body weight on disposition parameters was introduced using fixed allometric coefficients.
LUM-SDF PK was well described by a two-compartment disposition model with first-order absorption and first-order elimination; dose-under proportionality 960mg vs 480mg was described by a dose effect on relative bioavailability.
The exposure-response relationship was described by a logistic regression model relating Cday7 of lumefantrine to the probability of cure. KAF156 Cday7 did not have a statistically significant effect and was not retained in the model. Baseline parasitemia did not have a statistically significant effect and was not retained in the model. Age category (adolescents vs adults) was retained in the model, as the purpose of this analysis was to simulate doses in children 2-11 yeares old.
Simulations for children were performed using the established population PK models, assuming allometric coefficients and the exposure-response relationship in adolescents.
Conclusions: The established dose-exposure-response relationship supported the selection of doses for children 2-11 years old.
Reference: PAGE () Abstr 9360 [www.page-meeting.org/?abstract=9360]
Poster: Drug/Disease Modelling - Infection