ABSTRACT
Reduced levonorgestrel concentrations from the levonorgestrel contraceptive implant was previously seen when given concomitantly with efavirenz. We sought to assess whether single nucleotide polymorphisms (SNPs) in genes involved in efavirenz and nevirapine metabolism were linked to these changes in levonorgestrel concentration. SNPs in CYP2B6, CYP2A6, NR1I2, and NR1I3 were analyzed. Associations of participant demographics and genotype with levonorgestrel pharmacokinetics were evaluated in HIV-positive women using the levonorgestrel implant plus efavirenz- or nevirapine-based antiretroviral therapy (ART), in comparison to ART-naïve women using multivariate linear regression. Efavirenz group: CYP2B6 516G>T was associated with lower levonorgestrel log10 Cmax and log10 AUC. CYP2B6 15582C>T was associated with lower log10 AUC. Nevirapine group: CYP2B6 516G>T was associated with higher log10 Cmax and lower log10 Cmin . Pharmacogenetic variations influenced subdermal levonorgestrel pharmacokinetics in HIV-positive women, indicating that the magnitude of the interaction with non-nucleoside reverse transcriptase inhibitors (NNRTIs) is influenced by host genetics.
Subject(s)
Benzoxazines/administration & dosage , Contraceptive Agents, Female/administration & dosage , Levonorgestrel/pharmacokinetics , Nevirapine/administration & dosage , Reverse Transcriptase Inhibitors/administration & dosage , Adult , Alkynes , Area Under Curve , Constitutive Androstane Receptor , Contraceptive Agents, Female/pharmacokinetics , Cyclopropanes , Cytochrome P-450 CYP2A6/genetics , Cytochrome P-450 CYP2B6/genetics , Female , Genetic Variation , HIV Infections/drug therapy , Humans , Levonorgestrel/administration & dosage , Linear Models , Multivariate Analysis , Pharmacogenetics , Polymorphism, Single Nucleotide , Prospective StudiesABSTRACT
OBJECTIVE: To establish a relationship between angiotensin-converting enzyme (ACE) inhibitor therapy and renal outcomes in Medicaid patients with diabetes, and compare the use of ACE inhibitors between 1994 and 1998. METHODS: One thousand patients with either type 1 or type 2 diabetes were randomly selected from the Iowa Medicaid database and followed retrospectively from 1994 through 1998. Data on medication use (insulin, oral antidiabetic agents, or both) and medical services were collected from prescription claims and diagnostic codes. Differences were evaluated with nonparametric statistics. RESULTS: Overall, 402 patients (40.2%) were prescribed an ACE inhibitor during the study period before any adverse renal outcomes occurred; 25 of the patients in this group (6.2%) had a subsequent adverse renal outcome. One hundred patients (16.7%) not receiving an ACE inhibitor had an adverse renal outcome (p = 0.006). We evaluated four subgroups and found that patients with hypertension had fewer adverse renal outcomes if they were receiving ACE inhibitors whether they were taking (p = 0.0006) or not taking insulin (p = 0.047). There was no difference in adverse renal outcomes and ACE inhibitor use in normotensive patients who were taking (p = 0.15) or not taking insulin (p = 0.96). The pattern of use of ACE inhibitors in this population increased more than twofold between 1994 and 1998 (38.1% vs. 80.1%; p < 0.001). Of those patients who had adverse renal outcomes, almost one-half (43.2%) were not taking an ACE inhibitor in 1998. CONCLUSIONS: ACE inhibitors were renoprotective in patients with diabetes in the Iowa Medicaid population. All patients with diabetes who had hypertension had fewer renal outcomes when taking an ACE inhibitor. ACE inhibitors were used more frequently in 1998 than in 1994. The use of ACE inhibitors in this population is improving, but remains less than optimal.
