No abstract

Azithromycin (AZI) is an azalide antibiotic with antimalarial activity that is considered safe in pregnancy.To assess its pharmacokinetic properties when administered as intermittent preventive treatment in pregnancy (IPTp), two 2-g doses were given 24 h apart to 31 pregnant and 29 age-matched nonpregnant Papua New Guinean women. All subjects also received single-dose sulfadoxine-pyrimethamine (SP) (1,500 mg or 75 mg) or chloroquine (450-mg base daily for 3 days). Blood samples were taken at 0, 1, 2, 3, 6, 12, 24, 32, 40, 48, and 72 h and on days 4, 5, 7, 10, and 14 for AZI assay by ultra-high-performance liquid chromatography-tandem mass spectrometry. The treatments were well tolerated. Using population pharmacokinetic modeling, a threecompartment model with zero-order followed by first-order absorption and no lag time provided the best fit. The areas under the plasma concentration-time curve (AUC 0-ؕ ) (28.7 and 31.8 mg ⅐ h liter ؊1 for pregnant and nonpregnant subjects, respectively) were consistent with the results of previous studies, but the estimated terminal elimination half-lives (78 and 77 h, respectively) were generally longer. The only significant relationship for a range of potential covariates, including malarial parasitemia, was with pregnancy, which accounted for an 86% increase in the volume of distribution of the central compartment relative to bioavailability without a significant change in the AUC 0-ؕ . These data suggest that AZI can be combined with compounds with longer half-lives, such as SP, in combination IPTp without the need for dose adjustment.

Intermittent preventive treatment in infancy (IPTi) entails routine administration of antimalarial treatment doses at specified times in at-risk infants. Sulfadoxine-pyrimethamine (SDX/PYR) is a combination that has been used as first-line IPTi. Because of limited pharmacokinetic data and suggestions that higher milligram/ kilogram pediatric doses than recommended should be considered, we assessed SDX/PYR disposition, randomized to conventional (25/1.25 mg/kg of body weight) or double (50/2.5 mg/kg) dose, in 70 Papua New Guinean children aged 2 to 13 months. Blood samples were drawn at baseline, 28 days, and three time points randomly selected for each infant at 4 to 8 h or 2, 5, 7, 14, or 21 days. Plasma SDX, PYR, and N 4 -acetylsulfadoxine (NSX, the principal metabolite of SDX) were assayed by high-performance liquid chromatography (HPLC). Using population modeling incorporating hepatic maturation and cystatin C-based renal function, two-compartment models provided best fits for PYR and SDX/NSX plasma concentration profiles. The area under the plasma concentration-time curve from 0 h to infinity (AUC 0-ؕ ) was greater with the double dose versus the conventional dose of PYR (4,915 versus 2,844 g/day/liter) and SDX (2,434 versus 1,460 mg/day/liter). There was a 32% reduction in SDX relative bioavailability with the double dose but no evidence of dose-dependent metabolism. Terminal elimination half-lives (15.6 days for PYR, 9.1 days for SDX) were longer than previously reported. Both doses were well tolerated without changes in hemoglobin or hepatorenal function. Five children in the conventional and three in the double-dose group developed malaria during follow-up. These data support the potential use of double-dose SDX/PYR in infancy, but further studies should examine the influence of hepatorenal maturation in very young infants.Intermittent preventive treatment in infancy (IPTi) is a strategy in which infants in areas in which malaria is endemic are given treatment doses of antimalarial drugs at specified times, regardless of clinical and parasitologic status. Because of its availability, tolerability, and relatively low cost, sulfadoxinepyrimethamine (SDX/PYR) has been used as a first-line treatment in IPTi programs, especially in Africa. A recent review of safety and efficacy data from six trials conducted from 1999 to 2007 revealed that, despite the emergence of molecular markers of parasite resistance, SDX/PYR IPTi reduced clinical malaria and malaria-related hospital admissions by about onethird and reduced anemia in the first year of life by 15% (23). The duration of effective antimalarial prophylaxis after a dose of SDX/PYR is 4 to 6 weeks (9, 17).There is evidence that the efficacy of SDX/PYR IPTi is dose dependent. When given as a fixed dose (27), efficacy declines with age as lower doses (milligrams/kilogram of body weight) are taken (9). In addition, studies of older children aged 2 to 5 years with falciparum malaria have found higher clearance rates and larger apparent volumes of distribution for...