This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The Department of Health and Human Services recommends that therapies of known benefit not be withheld from pregnant women unless the risks clearly outweigh the benefits. Since 1997, antiretroviral therapy with a combination of approved anti-HIV agents has been the standard of care in the United States for those who meet treatment criteria, including pregnant women. Currently, treatment with the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine and lamivudine and a protease inhibitor (PI) is most frequently prescribed to pregnant women cared for through the Children's Hospital Immunodeficiency Program (CHIP) at The Children's Hospital. The Department of Health and Human Services (DHHS) Treatment Guidelines also recommend plasma therapeutic drug monitoring of PIs during pregnancy. Accordingly, CHIP performs plasma peak and trough levels of the PIs in pregnant women, and dose adjusts if trough levels are lower than expected. Several studies have demonstrated improved virologic suppression with therapeutic drug monitoring in non-pregnant individuals. In particular, AIDS Clinical Trials Group Study (ACTG) 359, a study examining sex-based differences in saquinavir (a PI) pharmacology and virologic response, demonstrated that males had a lower probability of having viral loads < 500 copies/mL at study endpoint than did females. This difference was attributed to the fact that females had higher plasma concentrations of saquinavir than did males. There have not yet been any longitudinal therapeutic drug monitoring studies conducted during pregnancy. [1]There is little information on the effect of pregnancy on antiretroviral drug pharmacokinetics. It is important to not only study the plasma pharmacokinetics of the antiretroviral drugs, but also to quantify the active moieties of these drugs since essentially all physiologic systems are altered during pregnancy. The active moieties of the NRTIs are the intracellular triphosphorylated parent drug. A sizable amount of plasma NRTI data are available, yet no data exist on the intracellular pharmacokinetics of the active triphosphorylated analyte of these agents during pregnancy. While the PIs do not require an intracellular transformation to exert their effect, they are highly protein bound agents. Only unbound drug is available to produce an effect. There are some studies that have intensively quantified plasma levels of the PIs during pregnancy, yet none have published information on unbound concentrations. This proposal aims to characterize the plasma, intracellular, and unbound pharmacokinetic disposition of antiretroviral agents during pregnancy and the pharmacokinetic efficacy of PI dosage adjustment. This study will enroll pregnant women who are cared for by CHIP at The Children's Hospital. Thirty pregnant women (less than 22 weeks gestation) will be entered into one of two groups.Abstract Table: Treatment CohortsGroup Nucleoside reverse transcriptase inhibitor (NRTI)* Protease Inhibitor (brand name) and FormulationI zidovudine + lamivudine nelfinavir (Viracept ) 625 mg tabletII zidovudine + lamivudine lopinavir/ritonavir (Kaletra ) 200/50 mg tablet*stavudine may be substituted for zidovudine in certain circumstances (see Section I)Group 1 will include women on zidovudine and lamivudine plus nelfinavir. Group 2 will include women on zidovudine and lamivudine plus lopinavir/ritonavir. Women who present to CHIP already on antiretroviral therapy which includes zidovudine and lamivudine plus nelfinavir or lopinavir/ritonavir may enroll without randomization. Otherwise, women who present to CHIP not already on therapy will be randomized to either nelfinavir or lopinavir/ritonavir and will be prescribed the NRTI combination zidovudine and lamivudine. In order to assure balance between the two groups, the randomization will control for the number of subjects on each arm; whereby the probability of being randomized to either arm is a function of the distribution of subjects already on study. Intensive plasma NRTI and PI sampling (9 determinations at 1-2 hour intervals) will occur once during the 2nd and 3rd trimesters. Also during these intensive pharmacokinetic visits, intracellular triphosphate concentrations (ICTP) of zidovudine and lamivudine will be determined at pre-dose and 4 hours post-observed dose, and unbound PI concentrations will be determined at pre-dose, 2-, 4-, and 8-hr post-observed dose. Pharmacologic evaluations will be conducted in real time by the University of Colorado Antiviral Pharmacology Laboratory (Director: CV Fletcher). These intensive pharmacokinetic profiles will allow for non-compartmental analysis of pharmacokinetic parameters, including the area-under-the-concentration-time curve (AUC) of the PIs. If the AUC value is below the historic population 25th percentile and/or the minimum concentration (Cmin) is below the 50th percentile, a dosage adjustment of the PI component will be recommended within two weeks of the intensive pharmacokinetic visit. Approximately two weeks following the dosage recommendation of the PI (whether adjusted, or not), another short study visit will take place to assess the trough bound and unbound concentrations of the PI, and blood will be collected for ICTP NRTI quantification. These short study visits will be repeated again following the third trimester intensive pharmacokinetic visit. Lastly, postpartum plasma trough levels of the antiretroviral drugs will be collected 2 weeks postpartum for those women who remain on antiretroviral therapy. Blood will once again be collected for ICTP quantification and unbound PI concentrations postpartum. An important component to pharmacokinetic analysis includes adherence counseling. Each study participant's adherence will be addressed by investigators during scheduled study visits, including a discussion of the necessary dietary requirements to obtain adequate absorption and reduced adverse effects attributed to each medication the patient is receiving. The importance of this study resides in the fact that it will generate plasma bound and unbound pharmacokinetic data for the 625 mg nelfinavir tablet formulation and for the 200/50 mg lopinavir/ritonavir tablet formulation. In addition, for the first time, ICTP NRTI levels will be measured during pregnancy. It will also provide information on the effectiveness of pharmacokinetic-guided dose adjustments of nelfinavir and lopinavir/ritonavir during pregnancy, and will allow a longitudinal description of individual pharmacokinetic parameters, beginning in the 2nd trimester and through the postpartum period.
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