Pharmacology Core Research
The Core provides support to AIDS researchers through study consultation and using state of the art methodologies for quantitating drugs. Projects include:
- PI Induced Metabolic Abnormalities: The Core provides ongoing support to Dr. Carl Grunfeld?s translational research on the metabolic effects of PIs and new ARVs. Over the past funding year we analyzed samples for several protease inhibitors with new manuscripts published (Taylor, Pao).
- Penetration of ARV into the Cerebrospinal Fluid: This Core provides ongoing support to Dr. Richard Price evaluating the penetration of ARVs into the CSF and comparing CSF exposure to plasma exposure.
- Drug-drug interactions between ethanol and ARVs (McCanz-Katz)
- Pharmacogenetic Studies: The Core supports pharmacogenetic (PG) studies through measurement of ARVs and antituberculosis medications: This includes projects sponsored by IMPAACT including an ongoing study of the PK, PG and toxicity of isoniazid and N-acetylisoniazid in HIV infected pregnant women linking variants of CYP2E1 and NAT2 to INH PK and toxicity.
- Basic Pharmacology of Antimalarial Drugs: Piperaquine is widely used clinically throughout sub-Saharan Africa. However, no information was available as to its mechanism of metabolism which has implications for treatment of HIV-malaria co-infected patients requiring multiple CYP drugs. Dr. Sunil Parkih showed that piperaquine is metabolized by CYP3A4 and 2C8 through support by this Core. A paper is submitted (Lee).
- Nevirapine Disposition and Toxicity in Women: The Core supports ARV PK/PD studies in women including evaluation of nevirapine disposition and toxicity in over 300 women treated in multiple sub-Saharan countries. Results indicated NVP exposure predicts grade 3+ rash in a small sub-set of women (Dong). In addition, the Core supported work evaluating drug-drug interactions between oral and transdermal hormones and PIs (Vogler).
- Malaria: ACT drugs are prone to clinically significant drug-drug interactions, and this Core has supported PK interaction studies with ARV drugs. Artemether-Lumefantrine (AL) is used widely in HIV co-infected patients and is subject to important drug-drug interactions. CFAR supported studies in the past year including investigating the impact of EFV on AL disposition (Huang, et al, manuscript in preparation).
- Tuberculosis: The Core supports drug-drug interactions studies between rifampin based TB treatment and efavirenz or nevirapine based ARV therapy (ACTG 5221) (Luetkemeyer). Additional work includes projects for TMC-207 (A5289, A5267, A5300) and PA-824 (A5306).
- Pediatric Antimalarial Pharmacology: The Core supports trials in children including our program of antimalarial pharmacology with CFAR investigators Drs. Phil Rosenthal, Grant Dorsey, Diane Havlir and Sunil Parikh and Ugandan investigators Drs. Moses Kamya and Julia Mwesigwa. In addition to the malaria work in children, this Core supports several ongoing pediatric studies within IMPAACT. Our preliminary pharmacology work resulted in funding of an R01 to decipher the PK/PD of antimalarial drugs in HIV co-infected children and pregnant women in Tororo, Uganda (Aweeka and Parikh, PIs). Ongoing analysis is underway for a study of lumefantrine and piperaquine in 200 very young children (aged 4 months to 2 years) based in Tororo, Uganda. Optimized assays continue to be developed and published (Huang).
In addition to our available services, new development continues in the following areas:
- Maraviroc Quantitation in Plasma: This assay underwent final review by the DAIDS funded Pharmacology Quality Assurance (PQA) Program. It is used to support the work of two CFAR projects: a) the relationship between ARV exposure and metabolic abnormalities (Grunfeld) and b) drug-drug interaction between ethanol and ARVs (McCanz-Katz).
- Lumefantrine Quantitation in Plasma: Assays for lumefantrine, the longer acting partner drug used as part of antimalarial combination therapies (ACT), were modified in the past year to permit quantitation of drug in very small capillary plasma volumes using LC tandem MS. The method supports multiple CFAR studies including the work of Drs. Diane Havlir and Grant Dorsey based in Tororo, Uganda. It has been particularly useful for measuring drug from plasma obtained by simple finger prick in very young children in Africa. It is also used to support a newly funded R01 that focuses on PK/PD of ACT in children and pregnant women in Tororo (Aweeka and Parikh, PIs). Lumefantrine assays are approved by the DAIDS PQA program.
- TMC207 and active M2 Quantitation in Plasma: This assay using LC tandem MS was developed for the exciting new diarylquinoline (DRAQ) antimycobacterial drug used for TB; TMC-207 and its active M2 metabolite. The assay was approved in this past year by the DAIDS PQA program. The methods are used to support the research of Drs. Annie Luetkemeyer and Havlir evaluating treatment strategies for HIV and TB coinfected patients and drug-drug interaction studies. In addition, current effort is to add M3 to the assay as this metabolite may have implications for toxicity and will help explain drug-drug interaction data now available.
- Small volume methods for ART and ACT drugs: Assays are being developed for small plasma volumes (e.g. 50-200 ÁL) and to allow measurement of multiple drugs simultaneously to support international pediatric studies carried out by CFAR investigators. Methods in development are for artemether, dihydroartemisinin, zidovudine, lamivudine, lopinavir/ritonavir and nevirapine.