Pharmacokinetics of Piperaquine and Lumefantrine in Young Children in Tororo Uganda

Pharmacokinetics of Antimalarial Medications in Ugandan Children

PI: F. Aweeka; Co-investigator: S. Parikh, M. Kamya, et al

Start Date: June 2007,

End Date: Dec, 2008

Funded by: CFAR, Drug Research Unit

This study in children with malaria investigated the pharmacology of artemether/lumefantrine and artesunate/amodiaquine in HIV un-infected children in Kampala, Uganda. It is expected that children will exhibit distinct differences in their pharmacokinetics compared to adults due to maturational effects in drug metabolism. Children (aged 5-13) were enrolled in the study. We evaluated the pharmacokinetics in Ugandan children aged 5-13 years with uncomplicated malaria treated with AL (n=20) or AQ/AS (n=21), with intensive sampling over 7 days following the last dose of 3 day regimens. Comparison to prior adult data suggests that LR exposure is lower in children and that AQ/DEAQ exposure is similar in children and adults. For the artemisinin drugs, differences between exposure in children and adults vary depending on which artemisinin is administered. PK distinctions between children and adults should be considered to optimize dosing strategies for these widely utilized ACT regimens.

Publication: 1: Mwesigwa J, Parikh S, McGee B, German P, Drysdale T, Kalyango JN, Clark TD,Dorsey G, Lindegardh N, Annerberg A, Rosenthal PJ, Kamya MR, Aweeka F. Pharmacokinetics of artemether-lumefantrine and artesunate-amodiaquine in children in Kampala, Uganda. Antimicrob Agents Chemother. 2010 Jan;54(1):52-9.Epub 2009 Oct 19. PubMed PMID: 19841149; PubMed Central PMCID: PMC2798532.

Pharmacokinetic Interactions between Antiretroviral Agents, Lopinavir/Ritonavir and Efavirenz and Antimalarial Drug Combinations, Artesunate/ Amodiaquine and Artemether/Lumefantrine

PI: F. Aweeka; Co-investigator: S. Parikh.

Start Date: June 2006; End Date: Dec 2011

Funding: CFAR, Drug Research Unit, Novartis, Inc.

Antimalarial drugs are prone to clinically significant drug-drug interactions with antiretroviral drugs. The drugs are very complex pharmacologically in that they are substrates for cytochrome P450 (CYP) isozymes and generally require activation to active metabolites. Artemether-lumefantrine (AL) and amodiaquine/artesunate are widely used to treat malaria in Uganda. For HIV co-infected children and adults, artemether/lumefantrine is perhaps the most widely prescribed ACT drug due to limited adverse effects. This study includes three (3) components for evaluating potential drug-drug interactions in healthy HIV sero-negative volunteers. The project was based at UCSF.. The first component evaluated the impact of efavirenz on amodiaquine/artesunate but was discontinued early due to unexpected hepatic toxicity in the first two subjects1 The second and third components evaluated the effect of lopinavir/ritonavir and efaviremz on the disposition of AL. Early results from our research carried out in healthy volunteers confirmed significant differences in AL disposition in the context of PI versus NNRTI regimens. AL was administered as a standard 3 day regimen both prior to and following the administration of lopinavir/ritonavir or efavirenz to steady state levels in HIV seronegative adults. The 7 day area under the concentration time curve for lumefantrine was increased (+200%, p<0.01)2 in the context of LPV/r but trended toward a decrease in the presence of EFV (-21%; p>0.05)3

Publications

1. German P, Greenhouse B, Coates C, Dorsey G, Rosenthal PJ, Charlebois E, Lindegardh N, Havlir D, Aweeka FT. Hepatotoxicity due to a drug interaction between amodiaquine plus artesunate and efavirenz. Clin Infect Dis. 2007 Mar 15;44(6):889-91. PubMed PMID: 17304470.

2. German P, Parikh S, Lawrence J, Dorsey G, Rosenthal PJ, Havlir D, Charlebois E, Hanpithakpong W, Lindegardh N, Aweeka FT. Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers. J Acquir Immune Defic Syndr. 2009 Aug 1;51(4):424-9. PubMed PMID: 19506482.

3. Huang L, Parikh S, Rosenthal PJ, Lizak P, Marzan F, Dorsey G, Havlir D, Aweeka FT. Concomitant efavirenz reduces pharmacokinetic exposure to the antimalarial drug artemether-lumefantrine in healthy volunteers. J Acquir Immune Defic Syndr. 2012 Nov 1;61(3):310-6. doi: 10.1097/QAI.0b013e31826ebb5c. PubMed PMID: 22918158

Pharmacokinetics of Piperaquine and Lumefantrine in Young Children in Tororo Uganda

PIs: S. Parikh; Co-investigators: F. Aweeka, G. Dorsey, M. Kamya, F. Nosten et al

Start Date: March 2008,

End Date: analysis ongoing

Funded by: Novartis, Inc, Holley-Cotec Pharmaceuticals

This study in very young children (aged 4 months to 2 years) has been based in Tororo, Uganda where 300 HIV infected and HIV uninfected children were enrolled for collection of PK samples for lumefantrine and piperaquine. Serial PK samples were collected and the data generated will provide information on drug disposition and the relationship between drug exposure and outcomes. In addition, the impact of factors such as weight and concomitant medications on PK exposure will also be evaluated.

Publication: Darren J. Creek1,2, Victor Bigira3, Shelley McCormack2, Emmanuel Arinaitwe3, Humphrey Wanzira3, Abel Kakuru3, Jordan W. Tappero4, Taylor G. Sandison5, Niklas Lindegardh6, Francois Nosten6,7,8, Francesca T. Aweeka2, Sunil Parikh2* Pharmacokinetic predictors for recurrent malaria after dihydroartemisinin-piperaquine treatment of uncomplicated malaria in Ugandan infants. JID, In Press, 2012