Drug-Drug Interaction Analysis of Pyronaridine/Artesunate and Ritonavir in Healthy Volunteers

A multiple dose, parallel group study was conducted to assess for a drug-drug interaction between the pyronaridine/artesunate (PA) combination antimalarial and ritonavir. Thirty-four healthy adults were randomized (1:1) to receive PA for 3 days or PA with ritonavir (100 mg twice daily for 17 days, PA administered on Days 8–10). Pharmacokinetic parameters for pyronaridine, artesunate, and its active metabolite dihydroartemisinin (DHA) were obtained after the last PA dose and for ritonavir on Days 1 and 10. Ritonavir coadministration did not markedly change pyronaridine pharmacokinetics but resulted in a 27% increase in artesunate area under the curve (AUC) and a 38% decrease in DHA AUC. Ritonavir exposure was increased 3.2-fold in the presence of PA. The only relevant safety observations were increases in liver enzymes, only reaching a clinically significant grade in the PA + ritonavir arm. It was concluded that coadministered ritonavir and PA interact to alter exposure to artesunate, DHA, and ritonavir itself.