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Data from Clinical Trials

2005; Lippincott Williams & Wilkins; Volume: 38; Issue: Supplement 1 Linguagem: Inglês

10.1097/01.qai.0000167036.48772.c8

1944-7884

Linda M. Catanzaro, Gene D. Morse,

Drug-Induced Hepatotoxicity and Protection

Introduction HIV-infected patients often receive hormone contraceptives along with other contraceptive approaches, with combined interventions reducing infection in women and subsequent maternal transmission to neonates. In many cases, these same patients may have been started on antiretroviral therapy. Whereas individual antiretroviral agents are often investigated with regard to drug–drug interactions during the early stages of the drug development process, the application of these two-way pharmacokinetic studies to patients receiving combination antiretroviral regimens, and possibly other interacting medications, presents a dilemma for the clinician. HIV-infected women taking hormone contraceptives as a sole method of contraception may be particularly at risk of negative drug interactions between antiretroviral agents and hormone contraceptives if the net effect is to lower plasma concentrations to a critical point at which ovulation occurs. Ethinyl Estradiol and Norethindrone Pharmacology Evaluations of the pharmacological effects of hormone contraceptives on oxidative drug metabolism date back to early work conducted at the time OCs were developed and sex differences in oxidative metabolism were being investigated1. Inherent differences in drug metabolism in animals was reported during studies of aminopyrine, hexobarbital and pentobarbital, with male rats being observed to have a three to five times more rapid metabolism. Data indicating that endogenous sex hormones utilized similar oxidative pathways to drugs were derived from studies examining the comparative effects of enzyme-inducing drugs and competitive inhibition experiments with steroid hormones1. The acute administration of estrogen or progesterone has an inhibitory effect, whereas chronic dosing (3 weeks) has an inducing effect resulting in increased metabolism. Pharmacokinetic Interactions Between Antiretroviral Agents and Hormone Contraceptives Pharmacokinetic Effects of Antiretroviral Agents on Hormone Contraceptives An important consideration in these drug interactions is the interpretation of pharmacokinetic data obtained when subjects are only administered the antiretroviral agent of interest with hormone contraceptives. These types of data are difficult to apply in the context of complex potent antiretroviral regimens when patients are also taking numerous other concurrent medications. Similarly, the application of these pharmacokinetic data to patients with hepatitis B or C co-infection as well as those patients with a varying severity of HIV disease requires further investigation. The antiretroviral regimen selected for an individual patient may vary as recommended by the current treatment guidelines, the patient's previous use of antiretroviral drugs and genotypic or phenotypic resistance tests. In general, antiretroviral drugs that induce metabolic pathways, such as ritonavir, nelfinavir, amprenavir, lopinavir, efavirenz and nevirapine, may elicit complex drug interactions with hormone contraceptives that may result in lower plasma concentrations of either ethinyl estradiol or norethindrone2–12. These effects are summarized in Tables 1 and 2.TABLE 1: Pharmacokinetic Effect of Non-nucleoside Reverse Transcriptase Inhibitors Co-administered with Oral ContraceptivesTABLE 2: Pharmacokinetic Effect of Protease Inhibitors Co-administered with Oral ContraceptivesFurthermore, as different patients may receive varying combinations, it is difficult to predict what the influence will be on ethinyl estradiol or norethindrone. For example, a naive patient may be receiving an OC with dual nucleosides and efavirenz as an initial regimen. Another patient may be on an OC, dual nucleosides with efavirenz, lopinavir and ritonavir. In the second patient, the interaction between OCs and efavirenz is complicated by the addition of lopinavir and ritonavir. Specific pharmacokinetic interaction data for these four drugs may be difficult to find and apply to a specific patient. The French guidelines recommend that these interaction data be utilized to individualize the prescription of OC13. Indinavir-associated increases in EE (24%) and norethindrone (26%) are addressed by recommending 15–20 μg EE. Interestingly, their recommendations for OC with efavirenz (use 15–20 μg EE) are accompanied by recommendations for nevirapine with higher doses (≥ 30 μg EE). Concurrent ritonavir, nelfinavir and lopinavir/ritonavir are recommended with higher doses (≥ 30 μg EE). The recommendation for EE dosing with efavirenz is consistent with the results from Joshi et al.2 which demonstrated a 37% increase in AUC of EE when co-administered with efavirenz in healthy individuals. As the enzyme induction activity of efavirenz usually predominates in most drug–drug interactions, this finding would not necessarily have been predicted. The recommendation to increase EE dosing when co-administered with nevirapine is also consistent with the findings of Mildvan et al.3, which showed a 29% decrease in AUC of EE in HIV-infected subjects. This is also consistent with the enzyme-inducing effect of nevirapine that would be expected. Pharmacokinetic Effects of Hormone Contraceptives on Antiretroviral Agents There is extensive literature describing animal and human studies investigating the influence of hormone contraceptives on a variety of different drugs and their metabolism. However, limited clinical studies have examined the influence of hormone contraceptives on antiretroviral pharmacokinetics beyond individual studies completed by the pharmaceutical manufacturer during the drug approval process. OCs may enhance the glucuronidation of certain compounds and increased oxazepam glucuronidation (conjugated by a similar isoform as zidovudine) has been reported14. On the basis of these data, the potential enhancement of zidovudine metabolism by OCs may lead to diminished plasma levels of the parent drug via increased glucuronidation. However, preliminary results from ACTG 317 have not demonstrated a significant difference in the glucuronidation of zidovudine in patients on OCs versus controls. This trial is ongoing and is also examining individuals who are receiving DMPA. Another ACTG trial, A5093, is investigating the pharmacokinetic interactions between DMPA and selected antiretroviral agents in HIV-infected women. The objectives are to determine the effect of DMPA on the pharmacokinetics of nelfinavir, indinavir, ritonavir, nevirapine and efavirenz, and to determine the effect of these antiretroviral agents on the pharmacokinetics of DMPA. As smoking may significantly decrease estrogen levels through the increased metabolism of estradiol, subjects enrolled in these types of pharmacokinetic studies should have their smoking history elicited. The mechanism involved is via polycyclic aromatic hydrocarbon induction of P450 CYP1A1 and CYP1A2. The use of ‘marker’ compounds to determine the level of CYP450 isoform activity has been advocated as a means of determining the level of activity or functional gene expression. This can be examined clinically with a single marker or as a ‘cocktail’15. For example, the ‘Cooperstown Cocktail’ has been reported and used for the intrasubject study of hormone contraceptive effects on CYP45016. Oral caffeine, dextromethorphan, omeprazole, warfarin and midazolam were administered (intravenously) for metabolic phenotyping. The investigators employed a crossover design in women with the five-drug cocktail on and off Ortho Tri-Cyclen® for 2 months of treatment, and then studied them at the beginning of week 4 of their menstrual cycle. Preliminary data indicate that a minimal change in CYP450 activity was noted17. Conclusion Applying pharmacokinetic data from drug interaction studies to patients with a varying severity of HIV disease is difficult, and may often be complicated by many interacting drugs being prescribed concurrently. More studies are needed to examine the ‘clinical’ situation of hormone contraceptives and antiretroviral agents in HIV-infected women. The complex scenarios that exist for HIV-infected women necessitate that alternative approaches be developed to obtain these data. Studies need to include a hormone contraceptive and antiretroviral evaluation during long-term administration. Pharmacogenomic applications including genotyping and phenotyping may offer promise for identifying patients at risk of experiencing important interactions. Population approaches employing therapeutic drug monitoring and real-time pharmacokinetic studies may also play a role.