Judianne C. Slish

A Gentamicin Pharmacokinetic Population Model and Once-Daily Dosing Algorithm for Neonates

Study Objective. To develop a gentamicin pharmacokinetic population model and once‐daily dosing algorithm for neonates younger than 10 days.

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.

Multidrug resistance 1 polymorphisms and trough concentrations of atazanavir and lopinavir in patients with HIV

INTRODUCTION HIV-infected patients receiving protease inhibitors may benefit from therapeutic drug monitoring-assisted dose adjustment to achieve target plasma concentrations. However, efflux pumps such as permeability-glycoprotein, which is encoded by the multidrug resistance (MDR)1 gene, may decrease intracellular drug concentrations, thus reducing the amount of drug at the site of action. Plasma concentrations of protease inhibitors and CD4 cell count response have been associated with the T allele at the MDR1 C3435T locus. We examined MDR1 single nucleotide polymorphisms in a cohort of patients in whom therapeutic drug monitoring is ongoing through a research protocol. METHODS In a multicenter study, genotypic analyses at two MDR1 loci, C3435T and G2677T, were performed by a real-time polymerase chain reaction method using DNA from 103 patients categorized as substance users or nonusers on atazanavir or lopinavir as the primary antiretrovirals. Allelic frequencies were determined as a function of racial/ethnic background, substance use status and trough concentrations of atazanavir and lopinavir. RESULTS The C/T and G/T alleles at the MDR1 C3435T and G2677T loci were equally frequent in the Caucasian population, but the wild-type alleles were more prevalent in the African-American population (59% homozygous [CC] and 32% heterozygous [CT] for C3435T; 80% homozygous [GG] and 16% heterozygous [GT] for G2677T). The frequencies in the Hispanic population were 46% CC and 38% CT for C3435T, and 58% GG and 38% GT for G2677T. No significant differences were seen in allele frequencies for MDR1 polymorphisms in substance user versus nonuser groups. Trough plasma concentrations of atazanavir or lopinavir were not correlated with the variant T allele. CONCLUSIONS These data confirm the higher prevalence of wild-type alleles of the MDR1 gene in African-Americans and the linkage disequilibrium between C3435T and G2677T loci. The T allele at the MDR1 C3435T and G2677T loci was not associated with higher atazanavir or lopinavir trough concentrations.

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.

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.

Management of HIV Infection in Persons Co-infected With Hepatitis

Co-infection with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) is becoming a rampant disparity in HIV-infected patients. The advent of antiretroviral therapy has led to agents that are effective for suppression of both HIV and HBV; however, this can not be extrapolated to patients who are coinfected with HCV. Treatment of HCV disease is often strenuous and can lead to untoward adverse effects. Co-infection with HIV often leads to higher rates of cirrhosis and liver failure in patients with HBV or HCV, compromising antiretroviral treatment in this patient population due to the hepatotoxicity of these agents. The purpose of this review is to familiarize health care providers to the management of HIV infection in patients who are also co-infected with HBV or HCV.