Pharmacokinetics and Pharmacodynamics of Antimalarial Agents: Optimizing Combination Therapies to Overcome Resistance Mechanisms.

Malaria remains a persistent global health challenge, worsened by the emergence of drug-resistant Plasmodium strains. This review synthesizes the pharmacokinetics (PK) and pharmacodynamics (PD) of key antimalarial agents, evaluating how these properties influence the performance of current pharmacological regimens. Findings in the literature indicate that artemisinin-based combination therapies (ACTs) achieve rapid parasite clearance by using short-acting artemisinin derivatives paired with longer-acting partner drugs. PK/PD modeling consistently demonstrates that well-matched half-lives and sustained post-treatment exposure are critical to prevent functional monotherapy-related resistance. Non-artemisinin and triple combination regimens show promise in overcoming multidrug resistance, but gaps remain in exposure-response characterization, dose alignment, and population-specific optimization. A discussion of PK/PD modeling across agents, including chloroquine, artemisinin and its derivatives, mefloquine, primaquine, and tafenoquine, highlights how inadequate drug exposure, mismatched partner drug kinetics, and host metabolic variability contribute to treatment failure. Collectively, the evidence suggests that refining combination regimens through PK/PD-guided dose optimization is crucial for maintaining efficacy and preventing resistance. Future research must prioritize host-specific factors, stage-specific drug activity, and optimized combination regimens to improve therapeutic outcomes and support malaria eradication.