Saliva as a potential matrix for evaluating pharmacologically active dolutegravir concentration in plasma.

Therapeutic drug monitoring (TDM) is used in certain clinically selected cases and in research settings to optimize the response to antiretroviral therapy. Plasma of blood is commonly used for TDM, but blood sampling is invasive and at risk for transmission of infectious agents. On the other hand, saliva sampling is noninvasive, safe, cheap, and easily performed compared to blood. Dolutegravir (DTG) is now widely prescribed as a key component of antiretroviral therapy for HIV infection. In this study, we examined the relationship between DTG concentrations in plasma and saliva of treated patients to explore the possibility of using saliva as an alternative body fluid of TDM. A total of 17 pairs of blood and saliva samples were obtained from 15 consented HIV-1-infected subjects treated with DTG containing regimens for more than one month. Both blood and saliva samples were collected within 1 h of each other. Drug concentrations were determined by liquid chromatography-tandem mass spectrometry using DTG-d5 as an internal standard. The LLOQ was 0.5 ng/mL. The calibration curves were prepared with pooled plasma or saliva containing DTG in a range of 0.5-100 ng/mL with precision of <14.4% and accuracy within ±14.7%. The DTG concentrations in the plasma and saliva were significantly correlated (Pearson's correlation coefficient r = 0.76, p < 0.001). The median ratio of the drug concentration in saliva to those in plasma was 0.0056, which is close to the rate of non-protein-bound DTG in plasma (0.70%), suggesting that only free DTG in plasma is transported to the salivary glands and secreted into saliva. The present study demonstrates that DTG concentration in saliva reflects the pharmacologically active drug concentration in plasma and may provide an easily accessible alternative for monitoring effective antiretroviral treatment.

Low plasmatic concentration of intensified antiretroviral therapy in a pregnant woman: a case report.

BACKGROUND: Identifying the most appropriate antiretroviral regimen for pregnant women with Human Immunodeficiency Virus (HIV-1) infection can be challenging, mainly due to pregnancy-related physiological alterations which can significantly reduce maternal drug plasma concentration. We would like to report our experience as it consists of an unusual case of low plasmatic concentration of antiretroviral drugs despite regimen intensification in a HIV-positive pregnant woman. It also underlines the need for accurate monitoring and treatment adjustment in pregnant women with Human Immunodeficiency Virus (HIV). CASE PRESENTATION: A 26-year-old Brazilian woman with HIV-1 infection attending our out-patient clinic presented with low plasmatic concentration of antiretroviral drugs and persistent detectable viral load despite regimen intensification during pregnancy. Trough plasma concentrations of dolutegravir and darunavir were measured by validated liquid chromatography-mass spectrometry. At 23 weeks of gestation it showed a lower value than expected in non-pregnant adults, compared to a normal level of plasma concentration measured at 10 weeks after delivery. Our patient and the baby had no regimen-related adverse effects. CONCLUSIONS: Physiological changes during pregnancy can affect pharmacokinetics and reduce a mother's bioavailability of antiretroviral drugs, potentially altering their pharmacological activity. A personalized treatment and a careful follow-up are hence mandatory for this key population.

Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection.

A long-acting injectable formulation of the HIV integrase inhibitor cabotegravir (CAB-LA) is currently in clinical development for PrEP. Although the long plasma half-life of CAB-LA is an important attribute for PrEP, it also raises concerns about drug resistance emergence if someone becomes infected with HIV, or if PrEP is initiated during undiagnosed acute infection. Here we use a macaque model of SHIV infection to model risks of drug resistance to CAB-LA PrEP. Six macaques infected with SHIV received CAB-LA before seroconversion. We show integrase mutations G118R, E92G/Q, or G140R in plasma from 3/6 macaques as early as day 57, and identify G118R and E92Q in viruses from vaginal and rectal fluids. G118R and G140R confer > 800-fold resistance to CAB and cross-resistance to all licensed integrase inhibitors. Our results emphasize the need for appropriate HIV testing strategies before and possibly shortly after initiating CAB LA PrEP to exclude acute infection.

A potential drug interaction between phenobarbital and dolutegravir: A case report.

In this report, we describe a human immunodeficiency virus (HIV)-infected patient in whom changes in phenobarbital (PB) dosage resulted in associated changes in plasma concentrations of dolutegravir (DTG). His plasma concentrations of DTG were 0.934, 0.584, 1.003 and 3.25 µg/mL, respectively, with concomitant daily PB doses of 40, 70, 30 and 0 mg, respectively. This case suggests that PB can lead to a remarkable reduction in the plasma concentration of DTG in a dose-dependent manner.

Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques.

A nanoformulated myristoylated dolutegravir prodrug (NMDTG) was prepared using good laboratory practice protocols. Intramuscular injection of NMDTG (118 ± 8 mg/ml, 25.5 mg of DTG equivalents/kg of body weight) to three rhesus macaques led to plasma DTG levels of 86 ± 12 and 28 ± 1 ng/ml on days 35 and 91, respectively. The NMDTG platform showed no significant adverse events. Further modification may further extend the drug's apparent half-life for human use.

Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1.

BACKGROUND: Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene polymorphisms (*6 and *28) in Japanese individuals infected with human immunodeficiency virus (HIV)-1 to examine the relationship between their plasma trough concentration of DTG and gene polymorphisms. Recently, neuropsychiatric adverse events (NP-AEs) after the use of DTG have become a concern, so the association between UGT1A1 gene polymorphisms and selected NP-AEs was also investigated. METHODS: The study subjects were 107 Japanese patients with HIV-1 infections who were receiving DTG. Five symptoms (dizziness, headache, insomnia, restlessness, and anxiety) were selected as NP-AEs. The subjects were classified by their UGT1A1 gene polymorphisms for the group comparison of DTG trough concentration and the presence or absence of NP-AEs. RESULTS: The subjects consisted of eight (7%) *6 homozygotes, three (3%) *28 homozygotes, four (4%) for *6/*28 compound heterozygotes, 23 (21%) *6 heterozygotes, 18 (17%) *28 heterozygotes, and 51 (48%) patients carrying the normal allele. The plasma DTG trough concentration of the *6 homozygous patients was significantly higher than that of the patients carrying the normal allele (median, 1.43 and 0.82 µg/mL, respectively, p = 0.0054). The *6 and *28 heterozygous patients also showed significantly higher values than those shown by patients with the normal allele. Multivariate analysis revealed that carrying one or two UGT1A1*6 gene polymorphisms, one UGT1A1*28 polymorphism, and age of < 40 years were independent factors associated with high DTG trough concentrations. The median DTG trough concentration was significantly higher in the patients with NP-AEs (1.31 µg/mL) than in those without NP-AEs (1.01 µg/mL). Consistent with these results, subjects carrying UGT1A1*6, UGT1A1*28, or both alleles showed a higher cumulative incidence of having selected NP-AEs than those carrying the normal alleles (p = 0.0454). CONCLUSION: In addition to younger age, carrying UGT1A1*6 and/or UGT1A1*28 was demonstrated to be a factor associated with high DTG trough concentrations. Our results also suggest a relationship between plasma DTG trough concentrations and NP-AEs, and that carrying UGT1A1*6 and/or UGT1A1*28 alleles might be a risk factor for NP-AEs.

A Two-Way Steady-State Pharmacokinetic Interaction Study of Doravirine (MK-1439) and Dolutegravir.

INTRODUCTION: Doravirine, a non-nucleoside reverse-transcriptase inhibitor in development for the treatment of patients with human immunodeficiency virus-1 infection, has potential to be used concomitantly in antiretroviral therapy with dolutegravir, an integrase strand transfer inhibitor. The pharmacokinetic interactions between these drugs were therefore assessed. METHODS: Oral formulations of doravirine and dolutegravir were dosed both individually and concomitantly once daily in healthy adults. Twelve subjects (six were male), 23-42 years of age, were enrolled and 11 completed this phase I, open-label, three-period, fixed-sequence study per protocol; one subject was discontinued for a positive cotinine test at admission to period 2. In period 1, dolutegravir 50 mg was administered for 7 days. After a 7-day washout, doravirine 200 mg was dosed for 7 days in period 2, followed (without washout) by both doravirine and dolutegravir simultaneously for 7 days in period 3. Plasma samples were taken to determine dolutegravir and doravirine concentrations. RESULTS: The steady-state concentration 24 h post-dose (C24) of dolutegravir was not substantially altered by co-administration of doravirine multiple doses; area under the plasma concentration-time curve from dosing to 24 h post-dose (AUC0-24), maximum concentration (C max), and C24 geometric mean ratios were 1.36, 1.43, and 1.27, respectively. The pharmacokinetics of doravirine was not affected by multiple doses of dolutegravir (geometric mean ratios: 1.00, 0.98, and 1.06 for AUC0-24, C24, and C max, respectively). Both drugs were generally well tolerated. CONCLUSION: The results of this study demonstrate that concomitant administration of doravirine and dolutegravir in healthy subjects causes no clinically significant alteration in the pharmacokinetic and safety profiles of the two drugs, thereby supporting further evaluation of co-administration of these agents for human immunodeficiency virus-1 treatment.

Dolutegravir plasma concentrations according to companion antiretroviral drug: unwanted drug interaction or desirable boosting effect?

BACKGROUND: Studies in healthy volunteers have shown that the recently approved HIV integrase inhibitor dolutegravir has limited drug-to-drug interaction profile. Here we carried out a pharmacokinetic survey in HIV-infected patients given dolutegravir as part of their antiretroviral therapy. METHODS: Dolutegravir plasma trough concentrations were measured in 78 HIV-infected patients given the drug in combination with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or abacavir/lamivudine. Drug concentrations were assessed by high performance liquid chromatography method with UV-detection. RESULTS: All patients were given dolutegravir at 50 mg once daily, with median trough drug concentrations of 1,096 (664-2,356) ng/ml (interindividual coefficient of variation: 85.3%). Patients given dolutegravir with atazanavir had significantly higher drug concentrations compared with those given darunavir, rilpivirine or abacavir/lamivudine (2,399 [1,929-4,070] versus 738 [552-1,048], 603 [432-1,373] or 1,045 [856-1,115] ng/ml; P<0.001 for all comparisons). By multivariate analyses, only companion antiretroviral drug resulted in significant association with dolutegravir plasma trough concentrations (P=0.012). CONCLUSIONS: Atazanavir coadministration significantly inhibited dolutegravir metabolism, ultimately resulting in a two- to fourfold increase in drug disposition compared with other antiretroviral drugs. This boosting effect of atazanavir could be used to optimize dolutegravir dosing in particular clinical settings.