Pharmacokinetics of Ruxolitinib in HIV Suppressed Individuals on Antiretroviral Agent Therapy from the ACTG A5336 Study.

Ruxolitinib is a US Food and Drug Administration-approved orally administered Janus kinase (1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, phase 2, open-label trial, ruxolitinib (10 mg twice daily) was administered to HIV-positive, virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART) for 5 weeks. Herein, we report the population PK subsequently determined from this study. Plasma concentrations of ruxolitinib (294 samples) and antiretroviral agents were measured at week 1 (N = 39 participants) and week 4 or 5 (N = 37). Ruxolitinib PK was adequately described with a 2-compartment model with first-order absorption and elimination with distribution volumes normalized to mean body weight (91.5 kg) and a separate typical clearance for participants administered efavirenz (a known cytochrome P450 3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical apparent oral clearance versus the integrase inhibitor regimen group (22.5 vs 12.9 L/hr; N = 14 vs 25). Post hoc predicted apparent oral clearance was likewise more variable and higher (P < .0001) in those administered efavirenz. There was  an ≈25% variation in ruxolitinib plasma exposures between week 1 and week 4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, integrase inhibitor-based ART regimens may be preferred over efavirenz-based regimens when ruxolitinib is administered to HIV-positive individuals.

Universal antiretroviral regimens: thinking beyond one-pill-once-a-day.

PURPOSE OF REVIEW: Poor adherence to oral antiretroviral treatment in a subpopulation of persons with HIV-1 infection interferes with the potential success of the drug regimens in treating the infection. Here, we review long-acting antiretroviral strategies currently in clinical development that could prove useful for the treatment of HIV-1 infection in individuals not succeeding with short-acting oral regimens. RECENT FINDINGS: Pharmaceutical nanotechnology has succeeded in creating two novel long-acting injectable antiretroviral compounds, carbotegravir and rilpivirine, which have completed early clinical trials demonstrating the safety, tolerability and prolonged antiretroviral activity. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA; MK8591) is a novel nucleoside reverse transcriptase inhibitor in early clinical development as a long-acting orally administered drug and in a long-acting polymer implant. Broadly neutralizing and cell-entry inhibitor monoclonal antibodies have demonstrated potent antiviral activity in early human trials; however, there is substantial baseline resistance. In addition, monotherapy leads to rapid resistance in those with baseline susceptibility. SUMMARY: Long-acting antiretroviral chemical compounds and monoclonal antibodies have demonstrated potent anti-HIV activity in the early-stage clinical investigations, and are actively being studied in advanced clinical trials for treatment and prevention. Strategies to manage toxicities and waning drug levels of chemical compounds, as well as primary and secondary resistance to current monoclonal antibodies are important considerations.

Compatibility of next-generation first-line antiretrovirals with rifampicin-based antituberculosis therapy in resource limited settings.

PURPOSE OF REVIEW: Reduced dose efavirenz, dolutegravir, and/or tenofovir alafenamide (TAF) are likely to be used in the next generation of first-line antiretroviral therapy in resource limited settings, where HIV-associated tuberculosis is common. Rifampicin, which is a key component of first-line antituberculosis therapy, is a potent inducer of many drug transporters and metabolising enzymes. We reviewed the literature for potential or actual drug--drug interactions between these antiretrovirals and rifampicin. RECENT FINDINGS: Dose adjustments of standard dose efavirenz are not necessary with rifampicin, because auto-induction of CYP2B6 by efavirenz counteracts the induction of rifampicin. However, patients with extensive metabolizer CYP2B6 genotypes have lower efavirenz concentrations and may have less auto-induction of CYP2B6; the additive inducing effects of rifampicin on CYP2B6 could result in clinically significant reductions of efavirenz concentrations. Doubling the dose of dolutegravir overcomes induction by rifampicin. TAF is more prone to be the victim in drug--drug interactions than tenofovir disoproxil fumarate. Interactions between TAF and rifampicin have not been studied, but there is likely to be significant interaction. SUMMARY: Further research on drug--drug interactions between rifampicin and the next generation of first-line antiretrovirals will be needed before they can be recommended in patients with HIV-associated tuberculosis.

Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment.

The year 2016 will mark an important milestone - the 35th anniversary of the first reported cases of HIV/AIDS. Antiretroviral Therapy (ART) including Highly Active Antiretroviral Therapy (HAART) drug regimens is widely considered to be one of the greatest achievements in therapeutic drug research having transformed HIV infection into a chronically managed disease. Unfortunately, the lack of widespread preventive measures and the inability to eradicate HIV from infected cells highlight the significant challenges remaining today. Moving forward there are at least three high priority goals for anti-HIV drug delivery (DD) research: (1) to prevent new HIV infections from occurring, (2) to facilitate a functional cure, i.e., when HIV is present but the body controls it without drugs and (3) to eradicate established infection. Pre-exposure Prophylaxis (PrEP) represents a significant step forward in preventing the establishment of chronic HIV infection. However, the ultimate success of PrEP will depend on achieving sustained antiretroviral (ARV) tissue concentrations and will require strict patient adherence to the regimen. While first generation long acting/extended release (LA/ER) DD Systems (DDS) currently in development show considerable promise, significant DD treatment and prevention challenges persist. First, there is a critical need to improve cell specificity through targeting in order to selectively achieve efficacious drug concentrations in HIV reservoir sites to control/eradicate HIV as well as mitigate systemic side effects. In addition, approaches for reducing cellular efflux and metabolism of ARV drugs to prolong effective concentrations in target cells need to be developed. Finally, given the current understanding of HIV pathogenesis, next generation anti-HIV DDS need to address selective DD to the gut mucosa and lymph nodes. The current review focuses on the DDS technologies, critical challenges, opportunities, strategies, and approaches by which novel delivery systems will help iterate towards prevention, functional cure and eventually the eradication of HIV infection.

Pharmacokinetic and metabolic effects of American ginseng (Panax quinquefolius) in healthy volunteers receiving the HIV protease inhibitor indinavir.

BACKGROUND: Complementary and alternative medicine (CAM) use is prevalent among HIV-infected patients to reduce the toxicity of antiretroviral therapy. Ginseng has been used for treatment of hyperglycemia and insulin resistance, a common side effect of some HIV-1 protease inhibitors (PI). However, it is unknown whether American ginseng (AG) can reverse insulin resistance induced by the PI indinavir (IDV), and whether these two agents interact pharmacologically. We evaluated potential pharmacokinetic interactions between IDV and AG, and assessed whether AG improves IDV-induced insulin resistance. METHODS: After baseline assessment of insulin sensitivity using the insulin clamp technique, healthy volunteers received IDV 800 mg q8 h for 3 days and then IDV and AG 1g q8h for 14 days. IDV pharmacokinetics and insulin sensitivity were assessed before and after AG co-administration. RESULTS: There was no difference in the area-under the plasma-concentration-time curve after the co-administration of AG, compared to IDV alone (n = 13). Although insulin-stimulated glucose disposal per unit of insulin (M/I) decreased by an average of 14.8 +/- 5.9% after 3 days of IDV (from 0.113 +/- 0.012 to 0.096 +/- 0.014 mg/kgFFM/min per muU/ml of insulin, p = 0.03, n = 11), M/I remained unchanged after co-administration of IDV and AG. CONCLUSION: IDV decreases insulin sensitivity, which is unaltered by AG co-administration. AG does not significantly affect IDV pharmacokinetics.

Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers.

AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C(max)), 934 h x ng/ml (313 to 2,127 h x ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C(max) of AMD070 [geometric mean (90% confidence interval)] by 39% (3 to 89%) and the AUC(0-infinity) by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.

The pharmacology of antiretroviral nucleoside and nucleotide reverse transcriptase inhibitors: implications for once-daily dosing.

The trend toward once-daily dosing in HIV antiretroviral therapy is based on the association between adherence, treatment outcome, and patient preferences. Patients prefer simpler treatments, fewer pills, less frequent dosing, and no food restrictions. When a regimen meets a patient's preferences, the patient is more likely to be adherent, and with good adherence, the regimen is more likely to be effective. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have been a prime focus for developing once-daily therapies primarily because they form the backbone of most current regimens. Within the NRTI class, however, drugs differ in their pharmacokinetic properties, such as plasma and intracellular half-lives, and thus in their suitability for once-daily dosing. For example, newer NRTIs, such as tenofovir and emtricitabine, combine longer plasma half-lives with longer intracellular half-lives, prolonging exposure and the period of pharmacologic activity. Of equal importance, the clinical impact of systemic and intracellular interactions between concomitant drugs defines which once-daily drugs may be combined in once-daily regimens. To construct simplified and effective therapies for individual patients, clinicians require an understanding of the plasma and intracellular pharmacokinetic properties of NRTIs and how these properties determine a drug's appropriateness for once-daily dosing and placement within a once-daily regimen.

Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection.

AMD3100 is a CXCR4 receptor inhibitor with anti-HIV-1 activity in vitro. We tested the safety, pharmacokinetics, and antiviral effect of AMD3100 administered for 10 days by continuous intravenous infusion in an open-label dose escalation study from 2.5 to 160 microg/kg/h. Forty HIV-infected patients with an HIV RNA level >5000 copies/mL on stable antiretroviral (ARV) regimens or off therapy were enrolled. Syncytium-inducing (SI) phenotype in an MT-2 cell assay was required in higher dose cohorts. Most subjects were black (55%), male (98%), and off ARV therapy. HIV phenotype was SI (30%), non-SI (45%), or not tested (25%). One patient (5 microg/kg/h) had serious and possibly drug-related thrombocytopenia. Two patients (40 and 160 microg/kg/h) had unexpected, although not serious, premature ventricular contractions. Most patients in the 80- and 160-microg/kg/h cohorts had paresthesias. Steady-state blood concentration and area under the concentration-time curve were dose proportional across all dose levels; the median terminal elimination half-life was 8.6 hours (range: 8.1-11.1 hours). Leukocytosis was observed in all patients, with an estimated maximum effect of 3.4 times baseline (95% confidence interval: 2.9-3.9). Only 1 patient, the patient whose virus was confirmed to use purely CXCR4 and who also received the highest dose (160 microg/kg/h), had a significant 0.9-log10 copies/mL HIV RNA drop at day 11. Overall, however, the average change in viral load across all patients was +0.03 log10 HIV RNA. Given these results, AMD3100 is not being further developed for ARV therapy, but development continues for stem cell mobilization.

Advances in HIV pharmacology: protein binding, pharmacogenomics, and therapeutic drug monitoring.

Developing better antiretroviral drugs, individualizing therapy through patient genetic profiling, and maintaining effective drug concentrations with therapeutic drug monitoring (TDM) represent 3 current areas of interest in the field of HIV pharmacology. This article first examines antiretroviral drug binding to plasma proteins, a factor that affects the amount of free drug available to enter cells. Protein binding influences drug development, raising questions about whether the drug levels required for appropriate therapeutic effect can be achieved at tolerable doses. Second, individualized antiretroviral therapy has generated considerable interest, but much work remains in the area of pharmacogenomics before this strategy finds a place in clinical practice. Finally, studies are mixed on the benefits of TDM; although such monitoring may be appropriate in some settings, such as pregnancy and pediatrics, data are currently lacking to support its routine use in HIV care. Although data on these pharmacologic strategies do not currently support their widespread clinical application, ongoing research of such strategies offers hope for future improvement of the efficacy of antiretroviral therapy. This article summarizes a presentation given by Charles W. Flexner, MD, at the November 2002 International AIDS Society-USA course in San Diego.

Alcohol use and HIV pharmacotherapy.

Alcohol consumption by individuals infected with HIV is an important medical management issue with significant implications for the effectiveness of antiretroviral therapy as well as an important evolving field of HIV research. Alcohol consumption is a risk factor for poor medication adherence and can modify liver drug metabolism, both of which can lead to the emergence of drug-resistant virus. Research indicates that alcohol consumption greater than 50 g/day (four or five drinks) is a risk factor for liver disease progression among patients with HIV/HCV coinfection. In addition, alcohol-induced cirrhosis can result in changes in drug metabolism in the liver through compromised liver function. More research studies are needed to elucidate the biological and molecular basis of the clinical changes induced by alcohol consumption in HIV-infected individuals and on the relationship of these changes to the effectiveness of HIV pharmacotherapy. Specifically, research areas that are of particular importance are (1) determining alcohol consumption levels and patterns and its impact on antiretroviral medication adherence, efficacy, and physician prescribing practices; (2) identifying behavioral interventions to enhance adherence to HIV medications and reduce alcohol consumption; (3) clarifying the relationships and interactions among alcohol metabolism, HIV drug metabolism, and pharmacogenetics; (4) elucidating the extent of liver toxicity due to antiretroviral therapy and drug-drug interactions in individuals who consume alcohol; and (5) delineating the contribution of alcohol consumption to end-stage organ damage, particularly in HIV/HCV coinfection.

Directly administered antiretroviral therapy in the treatment of HIV infection: benefit or burden?

While combination antiretroviral treatment has had a profound impact on the morbidity and mortality of human immunodeficiency virus (HIV) infection, the adherence demands of this therapy are high and failure to maintain viral suppression is common. Directly administered antiretroviral therapy (DAART) has garnered attention recently as a strategy to improve medication adherence and clinical outcomes in HIV-infected individuals. This review is intended to provide an update on the use of DAART and the challenges posed by this strategy, explore settings in which DAART may be used, discuss the role of antiretroviral regimens with improved pharmacokinetic features, and propose future directions for DAART strategies. DAART is modeled on directly observed therapy (DOT) for the treatment of tuberculosis. However, differences in curability, medication dosing frequency, duration of treatment, and the biologic dynamics of infection, pose unique challenges to DAART strategies. Numerous settings have been proposed for DAART, including community based outreach programs, prisons, long-term care facilities, substance abuse treatment sites, and resource-poor countries. Experience with DAART to date has been limited to pilot studies or retrospective comparisons. The prospect of simplified, once-daily antiretroviral therapy holds promise for DAART. However, improvements in antiretroviral therapy may also improve outcomes in patients taking therapy on a self-administered basis. Randomized controlled trials of DAART are needed before this strategy can be embraced in any setting. In future studies it will be important to compare DAART with self-administered therapy in terms of initial virologic and immunologic responses, durability of responses, the development of antiretroviral resistance, and cost effectiveness.