Pharmacokinetics of a Novel Piperaquine Dispersible Granules Formulation Under Fasting and Various Fed Conditions Versus Piperaquine Tablets When Fasted in Healthy Tanzanian Adults: A Randomized, Phase I Study

Abstract

Piperaquine tetraphosphate (PQP), a long-acting antimalarial, is being considered in a combination for chemoprevention. Dihydroartemisinin-piperaquine tablets (hard and dispersible) approved for the treatment of acute uncomplicated malaria should be administered in a fasted state, as PQP bioavailability increases with food. A new taste-masked dispersible granules PQP formulation aims to minimize the impact of food on drug exposure. This randomized, open label, parallel group, Phase I pilot study was conducted between 24th July 2023, and 3rd January 2024, at the Ifakara Health Institute, Bagamoyo, Tanzania in 60 healthy African adults (five cohorts of 12). Single-dose pharmacokinetics and relative systemic exposure of the oral PQP dispersible granules formulation prototype (320 mg) was compared to the hard tablet when fasted and PQP granules in three different fed conditions. In the fasted state, the relative exposure of PQP granules versus the tablet was 73.9% (90% CI 48.3, 113.0) for C_max and 86.5% (68.2, 109.6) for AUC_0-t. Following a typical East African low-fat meal, a standard high-fat meal, or 250 mL whole milk, the relative exposure of PQP granules versus the fasted state was 202% (90% CI 132, 311), 275% (193, 391), and 294% (203, 425) for C_max and 164% (124, 217), 184% (148, 228), and 195% (147, 259) for AUC_0-t, respectively. Both formulations were well tolerated with one drug-related adverse event (moderate migraine). No severe or serious adverse events or clinically relevant laboratory or electrocardiograph changes were observed. PQP dispersible granules had lower systemic exposures versus the tablet when fasted, whereas various meals increased drug exposure.