Effect of Prednisone on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

Abstract

Prednisone, a corticosteroid frequently used to treat common AIDS-related illnesses and comorbidities, has been shown to induce drug metabolism. This study was performed to determine whether prednisone coadministration affected the pharmacokinetics of dolutegravir (DTG). In this open-label, repeat-dose study, 12 healthy subjects were administered DTG at 50 mg daily alone for 5 days and then with concomitant prednisone for 10 days (prednisone at 60 mg daily for 5 days, followed by a 5-day taper). Serial blood sampling and safety assessments were performed during the trial. Pharmacokinetic parameters were determined using noncompartmental methods and geometric least-square mean ratios, and 90% confidence intervals were generated. Coadministration of DTG and 5-day high-dose prednisone with a 5-day taper had a modest effect on DTG exposure. The area under the DTG plasma concentration-time curve, maximum observed DTG concentration, and 24-hour postdose DTG concentration were increased by 11%, 6%, and 17%, respectively, on day 10 of the combination. Similar results were observed after 5 days of DTG and prednisone. Dolutegravir and prednisone coadministration was well tolerated. The changes in plasma exposures of DTG in healthy individuals as a result of prednisone dosing were not clinically significant. No dose adjustment is required for DTG coadministered with prednisone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01425099.)T argeting HIV integration of viral DNA into the human genome has yielded a new class of antiretroviral agents, the HIV integrase inhibitors, which have been used successfully in combination with other antivirals to suppress HIV replication (1-3). Dolutegravir (DTG; ViiV Healthcare, Research Triangle Park, NC) is a once-daily HIV integrase inhibitor with effective antiviral activity and a favorable safety profile. Dolutegravir is metabolized primarily by UDP-glucuronosyltransferase (UGT), with CYP3A4 playing a minor role (4). Dolutegravir has a favorable drug interaction profile, with few dose adjustments required, although potent enzyme inducers can reduce DTG exposure (5).Prednisone is used to treat a number of AIDS-related illnesses, such as immune reconstitution inflammatory syndrome, Pneumocystis jirovecii pneumonia, AIDS-related lymphoma, and concomitant diseases such as asthma, chronic obstructive pulmonary disease, autoimmune/rheumatologic disease, inflammatory bowel disease, and cancers (6-10).Some corticosteroids have been shown to decrease the exposure of UGT and CYP3A4 substrates (11, 12), depending on the choice of steroids, dose, and duration. Daily prednisone treatment of 40 mg/m 2 for 28 days increased etoposide clearance by 62% compared with placebo (13). Six-day treatment with low-dose prednisone (10 mg twice daily) modestly decreased metronidazole exposure, by 31% (14). Treatment with another corticosteroid, dexamethasone, at 1.5 mg for 4 days reduced oral triazolam AUC by 19% (15), whereas 2-day dexamethasone treatment at 24 mg per day decre...

Increased dose of Dolutegravir as a Potential Rescue Therapy in Multi-Experienced Patients

“…The five patients treated with the standard 50 mg dose of DTG had an average plasma concentration, 12 h after drug administration, of 3,233 ±875 ng/ml, in agreement with available pharmacokinetic studies [13], whereas the five patients treated with DTG 100 mg twice daily had an average plasma concentration, 12 h after drug administration, of 12,851 ±4,756 ng/ml ( Table 1). The fourfold difference in concentration between the two groups reveals that solubility does not seem to be an issue when 100 mg of DTG are administered as a single dose.…”

Cytochrome P450 enzyme regulation by glucocorticoids and consequences in terms of drug interaction

“…No clinically significant alteration of dolutegravir pharmacokinetics (50 mg/day) was observed in healthy volunteers after the 5-day coadministration of prednisone 60 mg/day followed by a 5-day taper [60].…”

Efficacy and safety of antiretrovirals in HIV-infected patients with cancer

“…The investigators stratified HIV-infected patients into three groups based on their ARV regimens: (i) non-NNRTI-based therapy, (ii) non-ritonavir PI-based therapy and (iii) ritonavir-based therapy; studies are in progress [17]. Dolutegrevir seems to have a safe drug interaction profile, making it a potential agent in the treatment of cancer patients with HIV infection [19]. PI-based treatment appears to greatly potentiate the myelotoxicity of chemotherapy [18].…”

“…Therefore, interactions of it with several commonly used anticancer drugs are expected. Dolutegrevir seems to have a safe drug interaction profile, making it a potential agent in the treatment of cancer patients with HIV infection [19].…”