Stronger activity of human immunodeficiency virus type 1 protease inhibitors against clinical isolates of Plasmodium vivax than against those of P. falciparum.

Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors (PIs) inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during human immunodeficiency virus type 1 (HIV-1) and malaria coinfection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic PIs, saquinavir (SQV) and ritonavir (RTV), against P. vivax (n = 30) and P. falciparum (n = 20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thailand-Myanmar border. The median 50% inhibitory concentration values of P. vivax to RTV and SQV were 2,233 nM (range, 732 to 7,738 nM) and 4,230 nM (range, 1,326 to 8,452 nM), respectively, both within the therapeutic concentration range commonly found for patients treated with these PIs. RTV was fourfold more effective at inhibiting P. vivax than it was at inhibiting P. falciparum, compared to a twofold difference in SQV sensitivity. An increased P. falciparum mdr1 copy number was present in 33% (3/9) of isolates and that of P. vivax mdr1 was present in 9% of isolates (2/22), but neither was associated with PI sensitivity. The inter-Plasmodium sp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum. PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients who reside in areas where multidrug-resistant P. vivax or P. falciparum is found.

The pharmacokinetics and pharmacodynamics of atovaquone and proguanil for the treatment of uncomplicated falciparum malaria in third-trimester pregnant women.

OBJECTIVE: To investigate the pharmacokinetics, safety and efficacy of the recommended 3-day treatment regimen of Malarone in third-trimester pregnant women with acute uncomplicated falciparum malaria. METHODS: Twenty-six pregnant women in their third trimester (gestational age: 24-34 weeks) with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrollment criteria were recruited from the antenatal clinics of Mae Sot Hospital, Tak Province, Thailand, (n = 8) and the Tropical Diseases Research Centre, Ndola, Zambia (n = 18). Patients were treated with four Malarone tablets (GlaxoSmithKline: each tablet contains 250 mg atovaquone and 100 mg proguanil) once daily for 3 consecutive days. Blood samples were taken for pharmacokinetic investigations of atovaquone, proguanil, and cycloguanil up to 288 h (day 14) after the last dose. Urine samples were collected for the evaluation of proguanil and cycloguanil 0-8, 8-16, 16-24 and 24-48 h after the last dose. Efficacy assessments included the clinical and parasitological evaluation of mothers and newborns. Adverse events were evaluated at each visit to the antenatal clinics. RESULTS: Malarone appeared to be effective and well tolerated when used for the treatment of falciparum malaria in pregnant women. All patients showed prompt clinical improvement and the disappearance of parasitaemia after treatment. There were no serious adverse effects or unexpected adverse effects and no stillbirths or spontaneous abortions. The plasma concentration-time profiles of atovaquone and proguanil in most cases were best characterised by the two-compartment open model with zero-order input with/without absorption lag time and first-order elimination. There were no significant differences in any of the pharmacokinetic parameters of atovaquone, proguanil or cycloguanil between patients from Thailand and Zambia. For atovaquone, a Cmax of 1.33-8.33 microg/ml was reached at 2.0-9.3 h after the last dose on day 2. V/F, CL/F and t(1/2beta) were 6.9-39.5 l/kg, 83-384 ml/h/kg, and 57.8-130.8 h, respectively. The Cmax and t(max) values for proguanil versus cycloguanil were 383-918 versus 0-129 ng/ml and 3.3-8.6 versus 3-12 h, respectively. V/F, CL/F, and t(1/2beta) values for proguanil were 10.7-34.0 l/kg, 431-1,662 ml/h/kg and 11.2-30.3 h. The CL(R-CG), t(1/2z), (CG), proguanil/cycloguanil metabolic ratios, AUC ratios for proguanil to cycloguanil (AUC(PG/CG)) were 107.2-1,001 ml/h/kg, 5-95 ml/h/kg, 7.8-20.7 h, 5-57, and 4.7-20.2, respectively. CONCLUSION: The pharmacokinetics of atovaquone and cycloguanil appeared to be influenced by the pregnancy status, resulting in an decrease in the Cmax and AUC of approximately twofold.