Experimental approaches to rational strategies for the prophylaxis and treatment of falciparum malaria

The chemoprophylaxis and treatment of malaria require thoughtful consideration of complex interacting factors: malaria biology and epidemiology, mechanisms of action and pharmacokinetics of antimalarial drugs, and highly variable individual host characteristics. An increasing number of overseas travelers between malaria non-endemic and endemic countries creates a greater demand for chemoprophyloxis. Widespread resistance of Plasmodium falciparum to antimalarial drugs has shortened the already-short list of drugs that are safe and effective for the prevention and treatment of malaria, especially in pregnancy. Co-prevalence of malaria and HIV in many malaria endemic regions further complicates the use of drugs to prevent or treat both of these infections. The need to evaluate the safety and efficacy of new antimalarial compounds and to develop pharmacokinetic- and pharmacodynamic-based approaches to improve the usefulness and safety of pre-existing drugs is urgent. In this thesis, incorporation of knowledge about drug, parasite and host factors in developing therapeutic strategies for the prophylaxis and treatment of malaria is discussed in the context of three clinical trials.;Phase I/II evaluation of the prophylactic antimalarial activity of DB289 in healthy volunteers challenged with Plasmodium falciparum. This is the primary project for this thesis. The study was a randomized, placebo-controlled, double-blind clinical trial designed to assess the causal prophylactic activity of DB289, a new investigational compound, in non-immune healthy volunteers challenged with P. falciparum. In this study, a dosing regimen for DB289 was developed by incorporating preclinical and clinical pharmacokinetic data and malaria biology to search for evidence of causal prophylactic activity. The data showed no evidence of reliable causal prophylactic activity of DB289 at the selected dose. Suppressive prophylactic activity remains to be evaluated.;Intermittent Preventive Treatment of malaria in pregnancy (IPTp). It is recommended that pregnant women living in areas with high malaria transmission be treated intermittently with a fixed-dosed drug combination, sulfadoxine-pyrimethamine, to prevent malaria-related complications. In the face of increasing drug resistance, the efficacy of this IPTp regimen is likely to be declining and yet no other safe, affordable and effective IPTp is available. I hypothesize that pharmacokinetic changes in pregnancy may result in the underdosing of these drugs, further compromising IPTp efficacy. To evaluate pregnancy-induced pharmacokinetic changes, a prospective clinical trial was designed to compare the pharmacokinetics of sulfadoxine-pyrimethamine during pregnancy and following the post-partum period in a self-matched fashion. The results of this ongoing study are expected to help develop a pharmacokinetic-pharmacodynamic-based dosing regimen to improve the usefulness of the current IPTp and inform future strategies for the prevention and treatment of malaria in pregnancy.;Interactions between antimalarial and antiretroviral drugs . The likelihood of clinically significant interactions between antimalarial and antiretroviral drugs is high. Many antimalarial drugs are the substrates of cytochrome P450 (CYP) enzymes, and a number of commonly-used antiretroviral drugs inhibit or/and induce these enzymes. A clinical trial was conducted to assess the pharmacokinetic interaction between a novel antiretroviral drug AMD070 and either of two probe drugs, the substrate of CYP3A4 or CYP2D6. The total exposure of both substrates was increased significantly in the presence of AMD070. Clinically important interactions may result when CYP3A4 and CYP2D6 substrates are used with AMD070. The design of this trial, including the use of probe drugs, may be applied in designing clinical studies assessing drug interaction between antimalarial and antiretroviral drugs.;Pharmacologic advances in the global control and treatment of malaria: combination therapy and drug resistance. Combining two or more antimalarial drugs has become an increasingly common practice in the treatment of falciparum malaria in endemic countries, to prevent or delay the development of drug resistance. The role of clinical pharmacology in the development of combination therapy is explored. The choice of partner drugs in a combination in a given population must consider their pharmacokinetic properties, the epidemiologic, immunologic, and transmission characteristics of malaria in that setting, and objectives of treatment (suppressive -vs- post-treatment prophylaxis). A one-size-fits-all approach may promote the development of resistant organisms and failure to achieve optimal results.