Linda M. Catanzaro

Clinical pharmacodynamics of HIV-1 protease inhibitors: use of inhibitory quotients to optimise pharmacotherapy

The introduction of HIV-1 protease inhibitors and non-nucleoside reverse transcriptase inhibitors in 1996 began an era described as that of highly active antiretroviral therapy. In addition, the more recent development and availability of HIV-1 genotypic and phenotypic resistance tests and advances in pharmacological assays that support therapeutic drug monitoring (TDM) have created tools that may help clinicians to provide more individualised treatment with HIV-1 protease inhibitors. All current treatment guidelines provide fixed doses of protease inhibitors with vague recommendations for the use of TDM in selected clinical situations. In patients with resistance to protease inhibitors, the combined use of resistance tests with TDM provide a mechanism for individualising the clinical pharmacodynamics of protease inhibitors. Current therapeutic approaches seek to include the monitoring of protease-inhibitor concentrations as part of a TDM programme with phenotypic assays to calculate an inhibitory quotient, virtual inhibitory quotient, or normalised inhibitory quotient, whereas genotypic tests are used with TDM to calculate a genotypic inhibitory quotient. Current investigation is focused on examining the predictive value of this approach for clinical monitoring.

Pharmacokinetic drug interactions with non-nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that inhibit HIV Type 1 reverse transcriptase. Although possessing a common mechanism of action, the approved NNRTIs, delavirdine, efavirenz and nevirapine, differ in structural and pharmacokinetic characteristics. Each of the NNRTIs undergoes biotransformation by the cytochrome P450 (CYP) enzyme system, thus making them prone to clinically significant drug interactions when combined with other antiretrovirals. In addition, they interact with other concurrent medications and complementary/alternative medicines, acting as either inducers or inhibitors of drug-metabolising CYP enzymes. These drug interactions become an important consideration in the clinical use of these agents when designing combination regimens, as recommended by current guidelines. This review provides an updated summary of pharmacokinetic interactions with NNRTIs.

Antiretroviral therapy : pharmacokinetic considerations in patients with renal or hepatic impairment.

Hepatic and renal insufficiency due to co-infection, alcoholism, diabetes mellitus, family history, adverse effects of antiretrovirals and other factors are commonly seen in HIV-infected patients. Therefore, the use of antiretrovirals in this patient setting requires attention to the pharmacokinetic issues that clinicians must consider when prescribing highly active antiretroviral therapy for these patients. This review summarizes the current knowledge of the use of antiretrovirals in patients with hepatic or renal impairment, and makes dosing recommendations for this subpopulation of HIV-infected patients.

Assessing the impact of substance use and hepatitis coinfection on atazanavir and lopinavir trough concentrations in HIV-infected patients during therapeutic drug monitoring

Atazanavir (ATV) and lopinavir (LPV) are widely used HIV-1 protease inhibitors. Like with other protease inhibitors, careful monitoring of potential drug-drug and drug-disease interactions in clinical practice is necessary. The aim of this study was to assess the impact of substance use and hepatitis virus coinfection on plasma ATV and LPV trough concentrations in HIV-positive substance users and nonusers. Individuals established on ATV (300 mg and 100 mg ritonavir daily) or LPV (400 mg and 100 mg ritonavir twice daily)-containing regimens completed two clinical visits (trough and directly observed therapy) during which dosing characteristics, concomitant medication, and substance use were recorded. Trough plasma concentrations (22-26 hours for ATV and 10-14 hours for LPV) were measured using LCMSMS. The influence of substance use was evaluated by Kruskal-Wallis test. Substance use was associated with a marked decrease in trough LPV concentrations during the trough visit (median, 5.536 and 3.791 μg/mL for nonsubstance users and substance users, respectively, P = 0.029). Significantly lower LPV trough levels were also noted among patients with active hepatitis C virus coinfection evaluated as an independent variable (median, 2.253 and 5.927 μg/mL for active and inactive/no hepatitis C virus infection, respectively, P = 0.032). Substance use and hepatitis virus coinfection had limited effects on ATV trough levels. In this cohort, despite the wide interindividual variability of ATV and LPV trough concentrations, significant associations between substance use and active hepatitis C virus infection and low LPV trough concentrations were observed. Further work is needed to assess the optimal dosing regimen when using LPV in HIV-infected substance users.

Update on the Pharmacokinetic Aspects of Antiretroviral Agents: Implications in Therapeutic Drug Monitoring

The observed inter-individual variation in antiretroviral pharmacokinetics (PK) that results in a wide range of drug exposures from fixed-dose regimens has led to increasing interest in the clinical use of therapeutic drug monitoring (TDM) to individualize dosing of antiretroviral therapy (ART). The focus of this review is to provide an overview of literature available to support therapeutic drug monitoring among the current classes of antiretrovirals, suggest patient populations that may benefit from TDM and bring forth some of the limitations that may exist for widespread use of TDM in a traditional clinical setting.

Macitentan for the Treatment of Pulmonary Arterial Hypertension

Objective: To review the pharmacology, safety, and efficacy of macitentan. Data Sources: PubMed, EMBASE, and ClinicalTrials.gov were searched using the terms macitentan and ACT-064992. Study Selection and Data Extraction: Phase II and III trials were reviewed in our primary analysis; data from phase I trials and other studies were reported as applicable. Data Synthesis: Macitentan is a dual endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH). Current treatment options for PAH include 2 other ERAs, phosphodiesterase type 5 inhibitors, prostanoids, and calcium channel blockers. Recently published guidelines do not assert a preference for individual agents. Two trials evaluated the safety and efficacy of macitentan. The phase II study was a 12-month placebo-controlled trial involving patients with idiopathic pulmonary fibrosis; the primary end point was change in forced vital capacity. No significant treatment effect was observed. The phase III study was a placebo-controlled trial involving patients with PAH. The primary end point was time to first occurrence of a composite of outcomes, including all-cause death and PAH worsening. Over a median period of 115 weeks, macitentan 10 mg and 3 mg daily significantly reduced morbidity and mortality. Commonly reported adverse effects included worsening of PAH, peripheral edema, upper-respiratory-tract infection, and anemia. Conclusions: Macitentan represents the latest addition to the PAH armamentarium. Compared with other ERAs, clinical advantages may include fewer contraindications, use in hepatic impairment, and once-daily administration. However, further comparative studies are necessary to ascertain its place in therapy.

Factors associated with altered pharmacokinetics in substance users and non-substance users receiving lopinavir and atazanavir.

Substance use is highly prevalent in HIV-infected individuals in the United States, and clinical management is complicated by the need for antiretroviral treatment, addiction therapy, variable medication adherence, and co-morbidities. The interrelation between HIV and substance use prompted our investigation to examine substance use and self-reported medication adherence in patients receiving the HIV-1 protease inhibitors, atazanavir (ATV) or lopinavir (LPV). ATV and LPV pharmacokinetics were determined by measuring plasma concentrations in subjects with active substance use (SU group) or with no active substance use (NSU group). No difference in adherence was observed between groups (p > 0.05). The mean SU ATV trough was 0.550+/-0.45 microg/mL; the mean NSU ATV trough was 0.780+/-0.590 microg/mL (p > 0.05). The mean SU LPV trough was 4.02+/-2.39 microg/mL; the mean NSU LPV trough was 6.67+/-0.910 microg/mL (p = 0.01). Co-factors found to be associated with variation in ATV and LPV concentrations included concurrent methadone use, cigarette smoking, and substance use status. These data indicate that chronic HIV treatment may be assisted with plasma concentration monitoring to identify those patients who may require dosage modification and/or regimen adjustment in order to optimize antiretroviral effects.

Therapeutic Drug Monitoring: Role for a Pharmacist in Multidisciplinary Antiretroviral Management:

The current treatment guidelines for HIV pharmacotherapy recommend combinations of antiretrovirals (ARVs) to achieve optimal suppression of HIV replication. However, the initiation and long-term management of ARV therapy in a patient is often complicated by variable medication adherence, complex medication use with multiple drug interactions, the occurrence of drug toxicity, and drug therapy for comorbid conditions that require additional patient education and laboratory monitoring. For these reasons, the inclusion of a well-trained pharmacist in multidisciplinary health system management strategies has been increasing. Furthermore, the use of fixed-dose ARVs is accompanied by considerable interpatient variation in pharmacokinetics yielding a range of drug exposures from any given ARV dose. One approach to overcoming this variable drug exposure is to use plasma concentration monitoring (eg, therapeutic drug monitoring [TDM]) as a clinical tool to adjust doses to achieve targeted concentration ranges, often in conjunction with HIV resistance tests. While data in support of TDM are emerging, the development of programs that include an HIV pharmaceutical care specialist and an adherence program with an integrated clinical pharmacology resource that can provide reliable TDM assays has been reported and provides the rationale for including pharmacists in the implementation of ARV TDM programs.