Browsing by Author "Back, David J."

Now showing 1 - 5 of 5
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    The Effect of Gene Variants on Levonorgestrel Pharmacokinetics when Combined with Antiretroviral Therapy containing Efavirenz or Nevirapine
    (Clinical Pharmacology & Therapeutics, 2017) Neary, Megan; Lamorde, Mohammed; Olagunju, Adeniyi; Darin, Kristin M.; Merry, Concepta; Byakika-Kibwika, Pauline; Back, David J.; Siccardi, Marco; Owen, Andrew; Scarsi, Kimberly K.
    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 analysed. Associations of participant demographics and genotype with levonorgestrel pharmacokinetics were evaluated in HIV-positive women using the levonorgestrel implant plus efavirenz- or nevirapine-based 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.
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    Steady-State Pharmacokinetics of Rilpivirine under Different Meal Conditions in HIV-1-Infected Ugandan Adults
    (Journal of Antimicrobial Chemotherapy, 2015) Lamorde, Mohammed; Walimbwa, Stephen; Kibwika, Pauline Byakika; Katwere, Michael; Mukisa, Lillian; Sempa, Joseph B.; Else, Laura; Back, David J.; Khoo, Saye H.; Merry, Concepta
    To investigate the effect of food on the steady-state pharmacokinetics of rilpivirine when administered as a fixed-dose combination tablet containing tenofovir disoproxil fumarate, emtricitabine plus rilpivirine (TDF/FTC/RPV) in HIV-1-infected Ugandan patients.This was an open-label, three-period, longitudinal pharmacokinetic study with patients serving as their own controls. Fifteen consenting and virologically suppressed HIV-1-infected adults were switched from an efavirenz-based regimen to TDF/FTC/RPV for 56 days. Enrolled patients underwent 24 h blood sampling with TDF/FTC/RPV dosing in the fasted state (day 42), with a low-fat meal (11 g of fat/353 kcal, day 49) and with a moderate-fat meal (19 g of fat/589 kcal, day 56; reference). A viral load assessment was performed on day 56.Rilpivirine AUC0–24 was significantly decreased by 16% (geometric mean ratio, 90% CI: 0.84, 0.73–0.96) during administration in the fasted state when compared with AUC0–24 during administration with a moderate-fat meal. Similarly, rilpivirine C24 was significantly decreased by 21% (0.79, 0.65–0.97) in the fasted state compared with a moderate-fat meal. Pharmacokinetic parameters were unchanged during administration with a low-fat meal, except for C24, which was significantly increased by 15% (1.15, 1.01–1.31) when compared with the moderate-fat meal. Rilpivirine Cmax was similar under the three meal conditions. Virological suppression was unchanged at the end of the study.A food effect was observed for steady-state pharmacokinetic parameters of rilpivirine (AUC0–24 and C24) when TDF/FTC/RPV was administered in the fasted state compared with the moderate-fat meal. The TDF/FTC/RPV formulation can be administered with either a low-fat or moderate-fat meal.
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    Steady-state pharmacokinetics of rilpivirine under different meal conditions in HIV-1-infected Ugandan adults
    (Journal of Antimicrobial Chemotherapy, 2015) Lamorde, Mohammed; Walimbwa, Stephen; Byakika-Kibwika, Pauline; Katwere, Michael; Mukisa, Lillian; Sempa, Joseph B.; Else, Laura; Back, David J.; Khoo, Saye H.; Merry, Concepta
    Over 24 million people are living with HIV in sub-Saharan Africa, the region that also experiences the highest prevalence of food insecurity. ART is the cornerstone for management of HIV, but few treatment options are available in African countries. The WHO recommends that first-line antiretroviral regimens should include one of two NNRTIs, either efavirenz or nevirapine. Although these drugs are efficacious, some patients may experience treatment-limiting toxicities, drug resistance or drug interactions with these agents; hence the need for more treatment options.
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    Suboptimal Nevirapine Steady-State Pharmacokinetics During Intrapartum Compared With Postpartum in HIV-1–Seropositive Ugandan Women
    (Journal of acquired immune deficiency syndromes, 2010) Lamorde, Mohammed; Byakika-Kibwika, Pauline; Okaba-Kayom, Violet; Flaherty, John P.; Boffito, Marta; Namakula, Rhoda; Ryan, Mairin; Nakabiito, Clemensia; Back, David J.; Khoo, Saye; Merry, Concepta; Scarsi, Kimberly K.
    Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa. Methods: This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNAwas performed within 2weeks of each visit. Nevirapine C12 above 3000 ng/mLwas classified as optimal based on the suggested value for therapeutic drug monitoring.
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    Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks
    (Clinical Infectious Diseases, 2016) Scarsi, Kimberly K.; Darin, Kristin M.; Nakalema, Shadia; Back, David J.; Byakika-Kibwika, Pauline; Else, Laura J.; Penchala, Sujan Dilly; Buzibye, Allan; Cohn, Susan E.; Merry, Concepta; Lamorde, Mohammed
    Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics. Methods. This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus–infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies.