cgp-56697 and Malnutrition

Malaria is an infectious disease which disproportionately effects children and pregnant women. These vulnerable populations are often excluded from clinical trials resulting in one-size-fits-all treatment regimens based on those established for a nonpregnant adult population. Pharmacokinetic/pharmacodynamic (PK/PD) models can be used to optimize dose selection as they define the drug exposure-response relationship. Additionally, these models are able to identify patient characteristics that cause alterations in the expected PK/PD profiles and through simulations can recommend changes to dosing which compensate for the differences. In this review, we examine how PK/PD models have been applied to optimize antimalarial dosing recommendations for young children, including those who are malnourished, pregnant women, and individuals receiving concomitant therapies such as those for HIV treatment. The malaria field has had great success in utilizing PK/PD models as a foundation to update treatment guidelines and propose the next generation of dosing regimens to investigate in clinical trials. We propose how the malaria field can continue to use modeling to improve therapies by further integrating PK data into clinical studies and including data on drug resistance and host immunity in PK/PD models. Finally, we suggest that other disease areas can achieve similar success in applying pharmacometrics to improve outcomes by implementing three key principals.

Topics: Amodiaquine; Anti-HIV Agents; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child, Preschool; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; Global Health; HIV Infections; Humans; Malaria; Malnutrition; Mefloquine; Models, Biological; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Quinolines; Sulfadoxine; Vulnerable Populations

It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates.. In a 2×2 factorial trial, 612 rural Tanzanian children aged 6-60 months in an area with intense malaria transmission and with height-for-age z-score≤-1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥ 8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191-296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93-1.18 and 1.10, 0.97-1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation.. We found no evidence from this trial that zinc supplementation protected against malaria.. ClinicalTrials.gov NCT00623857

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Dietary Supplements; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Incidence; Infant; Iron; Iron Deficiencies; Malaria; Malaria, Falciparum; Male; Malnutrition; Micronutrients; Prevalence; Regression Analysis; Tanzania; Zinc