Administration Of Efavirenz Research Articles

Oral Administration of Efavirenz Dysregulates the Tph2 Gene in Brain Serotonergic Areas and Alters Weight and Mood in Mice.

Most HIV-antiretroviral drugs have adverse effects. Efavirenz (EFV) is an example of a drug with neuropsychiatric effects, such as anxiety, depression, and suicidal thoughts, in people living with HIV (PLWH). The mechanisms by which EFV causes neuropsychiatric alterations in PLWH are complex, multifactorial, and not fully understood, although several studies in animals have reported changes in brain energy metabolism, alterations in monoamine turnover, GABA, and glutamate levels, and changes in 5-HT receptors. In this report, we studied the effects of EFV on the serotonergic system in healthy mice, specifically, whether EFV results in alterations in the levels of the tryptophan hydroxylase 2 (Tph2) gene in the brain. EFV (10 mg/kg) and distilled water (1.5 µL/kg) (control group) were orally administered to the mice for 36 days. At the end of the treatment, Tph2 expression levels in mouse brains were measured, and mood was evaluated by three trials: the forced swim test, elevated plus maze, and open field test. Our results revealed dysregulation of Tph2 expression in the brainstem, amygdala, and hypothalamus in the EFV group, and 5-HT levels increased in the amygdala in the EFV group. In the behavioral tests, mice given EFV exhibited a passive avoidance response in the forced swim test and anxiety-like behavior in the elevated plus maze, and they lost weight. Herein, for the first time, we showed that EFV triggered dysregulation of the Tph2 gene in the three serotonergic areas studied; and 5-HT levels increased in the amygdala using the ELISA method. However, further studies will be necessary to clarify the increase of 5-HT in the amygdala as well as understand the paradoxical decrease in body weight with the simultaneous increase in food consumption. It will also be necessary to measure 5-HT by other techniques different from ELISA, such as HPLC.

Influence of CYP2B6 Pharmacogenetics on Stereoselective Inhibition and Induction of Bupropion Metabolism by Efavirenz in Healthy Volunteers.

We investigated the acute and chronic effects of efavirenz, a widely used antiretroviral drug, and CYP2B6 genotypes on the disposition of racemic and stereoisomers of bupropion (BUP) and its active metabolites, 4-hydroxyBUP, threohydroBUP and erythrohydroBUP. The primary objective of this study was to test how multiple processes unique to the efavirenz-CYP2B6 genotype interaction influence the extent of efavirenz-mediated drug-drug interaction (DDI) with the CYP2B6 probe substrate BUP. In a three-phase, sequential, open-label study, healthy volunteers (N=53) were administered a single 100 mg oral dose of BUP alone (control phase), with a single 600 mg oral efavirenz dose (inhibition phase), and after 17-days pretreatment with efavirenz (600 mg/day) (induction phase). Compared to the control phase, we show for the first time that efavirenz significantly decreases and chronically increases the exposure of hydroxyBUP and its diastereomers, respectively, and these interactions were CYP2B6 genotype dependent. Chronic efavirenz enhances the elimination of racemic BUP and its enantiomers as well as of threo- and erythro-hydroBUP and their diastereomers, suggesting additional novel mechanisms underlying efavirenz interaction with BUP. The effects of efavirenz and genotypes were nonstereospecific. In conclusion, acute and chronic administration of efavirenz inhibits and induces CYP2B6 activity. Efavirenz-BUP interaction is complex involving time- and CYP2B6 genotype-dependent inhibition and induction of primary and secondary metabolic pathways. Our findings highlight important implications to the safety and efficacy of BUP, study design considerations for future efavirenz interactions, and individualized drug therapy based on CYP2B6 genotypes. Significance Statement The effects of acute and chronic doses of efavirenz on the disposition of racemic and stereoisomers of BUP and its active metabolites were investigated in healthy volunteers. Efavirenz causes an acute inhibition, but chronic induction of CYP2B6 in a genotype dependent manner. Chronic efavirenz induces BUP reduction and the elimination of BUP active metabolites. Efavirenz's effects were non-stereospecific. These data reveal novel mechanisms underlying efavirenz DDI with BUP and provide important insights into time- and CYP2B6 genotype dependent DDIs.

Long-term efavirenz exposure induced neuroinflammation and cognitive deficits in C57BL/6 mice

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI), which is widely used for anti-HIV-1. Evidences revealed that several central nervous system side effects could be observed in mice and patients with administration of EFV. However, the detailed mechanisms are still unknown. In this study, we investigated the effects of long-term EFV treatment on cognitive functions and the potential underlying mechanisms in mice. We maintained C57BL/6 mice aged 2 months with treatment containing 40 or 80 mg/kg/day EFV for 5 months, while control group treated with saline. The cognitive functions were evaluated by novel object recognition test, Barnes maze test and Morris water maze. The results showed significant short-term memory impairment in 40 and 80 mg/kg groups, and notable spatial learning and memory impairments in 80 mg/kg group, without any spontaneous activity alteration. Moreover, EFV induced impairments in dendritic integrity and synaptic plasticity in hippocampus. Furthermore, Significant increases were observed in the expression levels of pro-IL-1β, a similar tendency of TNF-α and phosphorylation of p65 of the 80 mg/kg group compared with control group. These results imply that long-term EFV treatment causes synaptic dysfunction resulting in cognitive deficits, which might be induced by the enhanced pro-inflammatory cytokines IL-1β and TNF-α via activating NF-κB pathway.

Development of reverse phase high-performance liquid chromatographic method for the estimation of HIV non-nucleoside reverse transcriptase inhibitor drug efavirenz in the rat brain

BackgroundThe brain is the potential viral reservoir, and estimating the antiviral drug concentration in the brain is a hurdle to the researchers as very few animal models are available for this study. The objective of the study was to develop and validate the RP-HPLC method for the estimation of antiviral drug efavirenz (EFV) in the brain of healthy Wistar rats. EFV was the first-line antiretroviral medication. The optimized HPLC condition used for the analysis had the mobile phase methanol to water (9:1) ratio. The flow rate was set at 0.8 mL/min, while the detection wavelength was 248 nm.ResultsThe retention time was found to be 5.7 min, and the % RSD was found within the limit. Recovery was found to be nearly 78%. The validation results were found to be within the limit range; hence, the obtained method was accurate, specific, rapid, and repeatable for estimation of EFV in the brain.ConclusionThis method for estimation of EFV in the rat brain can be applicable for pharmacokinetic and toxicology study of EFV in the brain after administration of EFV to rats.Graphical abstract.

Adverse Drug Reactions Associated with CYP 2B6 Polymorphisms in HIV/AIDS-Treated Patients in Yaoundé, Cameroon.

PurposeThe metabolism of antiretroviral drugs is subject to individual variations of the CYP 2B6 gene. The objective of this study was to evaluate the prevalence of CYP 2B6 516 G>T and 983 T>C polymorphisms and investigate their association with the development of adverse drug reactions (ADRs) in people living with HIV/AIDS in Cameroon.Patients and methodsA total number of 122 patients, attending the Yaoundé Central Hospital HIV Day Clinic, consented to take part in this study. Blood specimens were collected and DNA was extracted using the Chelex method. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was performed for the detection of CYP 2B6 Single-Nucleotide Polymorphisms (SNPs). Genotype frequencies were compared between groups with or without ADRs. Logistic regression analysis was performed to assess association between genotype and adverse effects of antiretroviral therapy (ART).ResultsThree types of metabolizers were identified: extensive, intermediate and slow. For the 516G>T polymorphism, prevalences of 8.2% GG, 65.6% GT and 26.2% TT were obtained. For the 983T>C polymorphism, 89.3% TT, 4.1% CT and 6.6% CC prevalences were obtained. Those homozygous for the wild-type allele (516GG) were less likely to develop ADR with a statistically significant difference (OR=0.885, P=0.029). For the CYP2B6 T983C SNP, homozygous mutants (CC) may present a higher risk (threefold) of developing adverse reactions (OR=2.677, P=0.164).ConclusionThese findings demonstrate that ADRs among HIV/AIDS patients under ART may be associated with the genetic variability of the metabolizing enzyme CYP 2B6. Genotyping for this gene may guide the better administration of Efavirenz and Nevirapine to Cameroonian patients.

Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz.

PurposeTo treat malaria, HIV-infected patients normally receive artemether (80 mg twice daily) concurrently with antiretroviral therapy and drug-drug interactions can potentially occur. Artemether is a substrate of CYP3A4 and CYP2B6, antiretrovirals such as efavirenz induce these enzymes and have the potential to reduce artemether pharmacokinetic exposure. The aim of this study was to develop an in vitro in vivo extrapolation (IVIVE) approach to model the interaction between efavirenz and artemether. Artemether dose adjustments were then simulated in order to predict optimal dosing in co-infected patients and inform future interaction study design.MethodsIn vitro data describing the chemical properties, absorption, distribution, metabolism and elimination of efavirenz and artemether were obtained from published literature and included in a physiologically based pharmacokinetic model (PBPK) to predict drug disposition simulating virtual clinical trials. Administration of efavirenz and artemether, alone or in combination, were simulated to mirror previous clinical studies and facilitate validation of the model and realistic interpretation of the simulation. Efavirenz (600 mg once daily) was administered to 50 virtual subjects for 14 days. This was followed by concomitant administration of artemether (80 mg eight hourly) for the first two doses and 80 mg (twice daily) for another two days.ResultsSimulated pharmacokinetics and the drug-drug interaction were in concordance with available clinical data. Efavirenz induced first pass metabolism and hepatic clearance, reducing artemether Cmax by 60% and AUC by 80%. Dose increases of artemether, to correct for the interaction, were simulated and a dose of 240 mg was predicted to be sufficient to overcome the interaction and allow therapeutic plasma concentrations of artemether.ConclusionsThe model presented here provides a rational platform to inform the design for a clinical drug interaction study that may save time and resource while the optimal dose is determined empirically. Wider application of IVIVE could help researchers gain a better understanding of the molecular mechanisms underpinning variability in drug disposition.

Effects of concurrent administration of efavirenz on the disposition kinetics of amodiaquine in healthy volunteers

Background/ObjectivesEfavirenz and amodiaquine are likely to be administered concurrently for the treatment of patients with HIV and malaria. The metabolism of amodiaquine is mediated principally by CYP2C8 while efavirenz is known to inhibit this enzyme. This study therefore investigated the effect of efavirenz on amodiaquine disposition. MethodsFourteen healthy volunteers were each given 600 mg single oral doses of amodiaquine alone or with the 9th dose of efavirenz (400 mg daily for 12 days) in a crossover fashion. Blood samples were collected at pre-determined time intervals and analyzed for amodiaquine and its major metabolite, desethylamodiaquine, using a validated HPLC method. ResultsCo-administration of amodiaquine and efavirenz resulted in significant increases (p < 0.05) in Cmax, Tmax, AUCT and elimination half-life (T1/2) of amodiaquine compared with values for amodiaquine alone. Also, efavirenz caused a pronounced decrease in the AUC (metabolite)/AUC (unchanged drug) ratio of amodiaquine along with a significant decrease (p < 0.05) in Cmax and AUC of the metabolite. ConclusionEfavirenz significantly alters the pharmacokinetics of amodiaquine, exposure to amodiaquine is increased leading to toxic effect, and reduction in the antimalarial activity since amodiaquine is a prodrug that relies on its active metabolite against malaria parasites.

In Vitro Analysis and Quantitative Prediction of Efavirenz Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effects on CYPs 2B6, 2C8, 2C9 and 2C19

In order to quantitatively predict drug interactions associated with efavirenz-based anti-HIV therapy, we evaluated reversible and time-dependent inhibitions of efavirenz on eight cytochrome P450 (CYP) enzymes in vitro. The present study showed that efavirenz was a potent competitive inhibitor of CYP2B6 (average K(i) = 1.68 µM in HLMs and K(i) = 1.38 µM in expressed CYP2B6) and CYP2C8 (K(i) = 4.78 µM in pooled HLMs and K(i) = 4.80 µM in HLMs with CYP2C8*3/*3 genotype). Efavirenz was a moderate inhibitor of CYP2C9 (K(i) = 19.46 µM) and CYP2C19 (K(i) = 21.31 µM); and a weak inhibitor of CYP3A (K(i) = 40.33 µM). No appreciable inhibition was observed on CYP1A2, CYP2A6 or CYP2D6. No time-dependent inhibition of the CYPs by efavirenz was observed in this study. Quantitative predictions showed that single dose of efavirenz may substantially slow the elimination of drugs predominantly cleared by CYP2B6, CYP2C19 or by both enzymes and may also lower the area under the plasma concentration time curve (AUC) of active metabolites of some pro-drugs (e.g., clopidogrel and proguanil) by up to 30%. Depending on substrates, chronic administration of efavirenz may increase the AUC of CYP2C8 and CYP2C9 substrates about 3.5-4.4-fold and 1.7-2.0-fold at steady state.

Biochemical effects of chronic administration of efavirenz on the intracranial auditory relay centers of adult Wistar rats

The biochemical effects of chronic administration of efavirenz, which is commonly used as part of highly active antiretroviral therapy for treatment of human immunodeficiency virus (HIV) type 1, on the intracranial auditory relay centers [i.e., the inferior colliculus (IC) and medial geniculate body (MGB)] of adult Wistar rats were carefully studied. Rats of both sexes (n = 30), with an average weight of 200 g, were randomly assigned into treatment (n = 15) and control (n = 15) groups. Rats in the treatment group each received the recommended daily dose of 600 mg/70 kg (1.71 mg/200 g) of body weight of efavirenz daily for 30 days, while the control group rats received an equal volume of distilled water alone daily for 30 days. The rats were sacrificed after 30 days, and the IC and MGB were carefully removed for further biochemical assays. These analyses indicated that levels of malonyldialdehyde (MDA), a non-enzyme biomarker of oxidative stress, were significantly higher (p < 0.05) whereas levels of superoxide dismutase (SOD) were significantly lower (p < 0.05) in treated tissues than in control tissues. Chronic administration of efavirenz may therefore have an adverse effect on the auditory sensibilities by affecting the IC and MGB of adult Wistar rats.

8.0 Antiretroviral therapy in specific populations

8.0 Antiretroviral therapy in specific populations

Induction of CYP2C19 and CYP3A Activity Following Repeated Administration of Efavirenz in Healthy Volunteers

Drug-drug interactions involving efavirenz are of major concern in clinical practice. We evaluated the effects of multiple doses of efavirenz on omeprazole 5-hydroxylation (CYP2C19) and sulfoxidation (CYP3A). Healthy volunteers (n = 57) were administered a single 20 mg oral dose of racemic omeprazole either with a single 600 mg oral dose of efavirenz or after 17 days of administration of 600 mg/day of efavirenz. The concentrations of racemic omeprazole, 5-hydroxyomeoprazole (and their enantiomers), and omeprazole sulfone in plasma were measured using a chiral liquid chromatography-tandem mass spectrometry method. Relative to single-dose treatment, multiple doses of efavirenz significantly decreased (P < 0.0001) the area under the plasma concentration-time curve from 0 to infinity (AUC(0-∞)) of racemic-, R- and S-omeprazole (2.01- to 2.15-fold) and the corresponding AUC(0-∞) metabolic ratio (MR) for 5-hydroxyomeprazole (1.36- to 1.44-fold) as well as the MR for omeprazole sulfone (∼2.0) (P < 0.0001). The significant reduction in the AUC of 5-hydroxyomeprazole after repeated efavirenz dosing suggests induction of sequential metabolism and mixed inductive/inhibitory effects of efavirenz on CYP2C19. In conclusion, efavirenz enhances omeprazole metabolism in a nonstereoselective manner through induction of CYP3A and CYP2C19 activity.

Effects of chronic administration of efavirenz on DNA of the intracranial visual relay centers of adult Wistar rats

The effects of chronic administration of efavirenz commonly used as part of Highly Active Antiretroviral Therapy (HAART) for the treatment of Human Immunodeficiency Virus (HIV) type-1 therapy on the DNA of the intracranial visual relay centre namely the superior colliculus and lateral geniculate body of adult Wistar rats were carefully studied. The rats of both sexes (n=20), with an average weight of 200g were randomly assigned into treatment (n=10) and control (n=10) groups. The rats in the treatment group received 600mg/70kg bogy weight of efavirenz dissolved in distilled water daily for 30 days through the orogastric tube. The control group received equal volume of distilled water daily for 30 days through the same route. The rats were fed with grower’s mash obtained from Edo Feeds and Flour Mill Limited, Ewu, Edo State, Nigeria and given water liberally. The rats were sacrificed by cervical dislocation method on the thirty-first day of the experiment. The superior colliculus and lateral geniculate body were carefully dissected out and quickly fixed in 10% formal saline for histochemical study. The histochemical findings indicated that the treatment sections of the superior colliculus and lateral geniculate body showed less intense staining and appeared pachychromatic. The stained neurons and glia cells were few as compared to the control sections. There were observations of neuronal enlargement in the superior colliculus and lateral geniculate body of the treated sections. The superior colliculus of the treated rats showed evidence of hypertrophy and microcytic changes in the darkly stained DNA positive granules, while the treated section of the lateral geniculate body showed positively stained DNA granules of various sizes and shapes, with an indication of hypertrophy and microcytic changes as compared to the control group. Chronic administration of efavirenz may therefore have an adverse effect on the DNA of the superior colliculus and lateral geniculate body of adult Wistar rats. It is recommended that further studies aimed at corroborating these observations be carried out.

Population Pharmacokinetics of Lopinavir/Ritonavir (Kaletra) in HIV-Infected Patients

A relationship between plasma concentrations and viral suppression in patients receiving lopinavir (LPV)/ritonavir (RTV) has been observed. Therefore, it is important to increase our knowledge about factors that determine interpatient variability in LPV pharmacokinetics (PK). The study, designed to develop and validate population PK models for LPV and RTV, involved 263 ambulatory patients treated with 400/100 mg of LPV/RTV twice daily. A database of 1110 concentrations of LPV and RTV (647 from a single time-point and 463 from 73 full PK profiles) was available. Concentrations were determined at steady state using high-performance liquid chromatography with ultraviolet detection. PK analysis was performed with NONMEM software. Age, gender, height, total body weight, body mass index, RTV trough concentration (RTC), hepatitis C virus coinfection, total bilirubin, hospital of origin, formulation and concomitant administration of efavirenz (EFV), saquinavir (SQV), atazanavir (ATV), and tenofovir were analyzed as possible covariates influencing LPV/RTV kinetic behavior. Population models were developed with 954 drug plasma concentrations from 201 patients, and the validation was conducted in the remaining 62 patients (156 concentrations). A 1-compartment model with first-order absorption (including lag-time) and elimination best described the PK. Proportional error models for interindividual and residual variability were used. The final models for the drugs oral clearance (CL/F) were as follows: CL/F(LPV)(L/h)=0.216·BMI·0.81(RTC)·1.25(EFV)·0.84(ATV); CL/F(RTV)(L/h) = 8.00·1.34(SQV)·1.77(EFV)·1.35(ATV). The predictive performance of the final population PK models was tested using standardized mean prediction errors, showing values of 0.03 ± 0.74 and 0.05 ± 0.91 for LPV and RTV, and normalized prediction distribution error, confirming the suitability of both models. These validated models could be implemented in clinical PK software and applied to dose individualization using a Bayesian approach for both drugs.

Influence of Efavirenz and Nevirapine on the Pharmacodynamics and Pharmacokinetics of Gliclazide in Rabbits

Background : Since polypharmacy is very common practice in diabetic patients, the study of drug-drug interactions is an imperative rational approach with respect to safety and efficacy determination. Gliclazide is a widely used drug for the treatment of type 2 diabetes. Efavirenz and nevirapine are widely used non-nucleoside reverse transcriptase inhibitors (NNRTIs) with fewer side effects concerning diabetic complications.The objective of the study is to investigate the effect of selected NNRTIs on the pharmacodynamics and pharmacokinetics of gliclazide in rabbits with respect to safety and efficacy of the combination. Methods : Influence of selected NNRTIs on the activity of gliclazide was determined by conducting a single dose interaction followed by multiple dose interaction study with two groups consisting of 6 normal rabbits each. Each group was treated with an oral dose of 5.6 mg/1.5 kg bd. wt. of gliclazide, interacting drug treatment (42 mg/1.5 kg bd. wt. of efavirenz or 14 mg/1.5 kg bd. wt. of nevirapine) and their combination with a one week washout period between each treatment. One week washout after this single dose interaction study, each group was continued with the daily treatment of interacting drug for the next eight days and then the combined treatment on the ninth day. Blood samples were collected at regular intervals by marginal ear vein puncture in rabbits and were analyzed for blood glucose by GOD/POD method and insulin by radioimmunoassay method. The serum gliclazide levels were estimated by HPLC method and pharmacokinetic analysis was conducted by noncompartmental analysis using WinNonlin software. Results : In combination, efavirenz significantly (P less than 0.05) reduced the pharmacodynamic activity and serum levels of gliclazide. The pharmacokinetic parameters of gliclazide were significantly (P less than 0.05) altered. The percent decrease of serum gliclazide concentration level is 24.23% and 15.20% following single dose and multiple dose administration of efavirenz, respectively. In combination, nevirapine has no significant effect on the pharmacodynamics and pharmacokinetics of gliclazide in rabbits. Conclusions : The significant pharmacokinetic interaction of efavirenz at metabolic level by CYP3A4 induction results in decreased serum gliclazide levels and pharmacodynamic activity of gliclazide. The combination of nevirapine and gliclazide was proved to be safe. doi:10.4021/jem34w

Efavirenz is a substrate and in turn modulates the expression of the efflux transporter ABCG2/BCRP in the gastrointestinal tract of the rat

The oral bioavailability of the antiretroviral efavirenz (EFV) undergoes high inter and intra-individual variability, this fact supporting its therapeutic drug monitoring. Previously, it was demonstrated that the encapsulation of EFV within polymeric micelles increases the oral bioavailability of the drug. The breast cancer resistant protein (BCRP, ABCG2) is known to be inhibited by EFV in vitro. Since ABCG2 is profusely expressed in the gastrointestinal tract, the aim of the present work was to thoroughly investigate whether the intestinal permeability of EFV is modulated by ABCG2. The functional role of ABCG2 in mediating the transport of EFV at the intestinal level was consistent with the following findings: (a) an ABCG2 inhibitor, fumitremorgin C (5–10μM), significantly potentiated the mucosal-to-serosal permeation of the drug in everted gut sacs; (b) a five-day oral treatment with 20mg/kg EFV promotes the over-expression of ABCG2 in about 100%, this phenomenon being accompanied by a clear decline in the intestinal permeability of the antiretroviral and (c) the normalization of the ABCG2 expression within 24h after the last administration of EFV was coincident with the recovery of the ability of the drug to permeate through the small intestine wall. Interestingly, no interactions between EFV and P-glycoprotein (ABCB1) were apparent. Since the intestinal permeability of a drug could be associated with its in vivo absorbability, we suggest that the oral absorption of EFV is affected by modifications in the ABCG2 intestinal expression contributing to the intra-individual bioavailability variations.

Morphological effects of chronic efavirenz administration on the kidney of adult Wistar rats

Efavirenz is commonly used as part of the highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) type 1. The effects of chronic administration of efavirenz on the kidney of adult Wistar rats were investigated. The rats were divided into two groups, those given efavirenz (treatment) and those given water (control), both for 30 days. The animals were sacrificed by cervical dislocation on Day 31 of the experiment and kidneys were dissected, weighed and quickly fixed in 10% formalin for histological analysis. The findings indicate that there was a significant ( p < 0.05) decrease in weight and increase in relative weight of treated right and left kidneys compared to the control group. Kidneys in the treated group showed disruption of the cytoarchitecture of the renal cortical structure, diffuse glomerulonephritis with some cell congestion, and dilation of Bowman’s space compared to the control group. Chronic efavirenz administration may therefore have an adverse effect on the kidney function of adult Wistar rats. Further studies to corroborate these observations should be carried out.

Pharmacokinetic Parameters of Once-Daily Rilpivirine following Administration of Efavirenz in Healthy Subjects

Rilpivirine and efavirenz share metabolic pathways (CYP3A), potentially leading to drug-drug interactions. We report the pharmacokinetics, ex vivo antiviral activity and safety of rilpivirine, following efavirenz treatment. HIV-negative adults received in fixed sequence: treatment A (rilpivirine 25 mg once daily for 14 days, followed by a washout), treatment B (efavirenz 600 mg once daily for 14 days), immediately followed by treatment C (rilpivirine 25 mg once daily for 28 days). Rilpivirine pharmacokinetic profiles were determined on days 1 and 14 of treatment A and days 1, 14, 21 and 28 of treatment C. Ex vivo antiviral activity was measured in treatments A and C using an exploratory assay. Safety was evaluated throughout. From days 1 to 21, higher mean rilpivirine exposure was observed with treatment A compared with treatment C. The area under the concentration-time curve (AUC(24 h)) least squares (LS) means ratio (90% CI) for treatment C versus treatment A was 0.54 (0.46, 0.64; Day 1), 0.82 (0.75, 0.89; Day 14) and 0.84 (0.74, 0.94; Day 21). By day 28 of treatment C, the main rilpivirine pharmacokinetic parameters were similar to day 14 of treatment A (AUC(24 h) LS means ratio [90% CI], 0.91 [0.82, 1.01]), except for the minimum plasma concentration. At each time point in treatment C, samples of >80% of subjects demonstrated similar ex vivo antiviral activity compared with treatment A. All adverse events were grade 1 or 2. These results provide useful information supporting a clinical study evaluating HIV-1-positive subjects switching from efavirenz to rilpivirine.

Effects of Chronic Administration of Efavirenz on the Inferior Colliculus of Adult Wistar Rats

Efavirenz is used for highly active antiretroviral therapy for the treatment of human immunodeficiency virus type-1. We studied the effect of chronic administration of efavirenz on the inferior colliculus of adult Wistar rats. Rats of both sexes (n = 16) were randomly assigned into treatment (n = 8) and control (n = 8) groups. The treatment group received 600 mg/70 kg body weight of efavirenz dissolved in distilled water daily for 30 days through an orogastric tube, and controls received distilled water. The rats were sacrificed on the 31st day of the experiment. We found that treated rats had cellular degenerative changes such as a sparse cellular population, hypertrophy, microcystic changes, and vacuolation in the stroma of the inferior colliculus in treated rats compared with controls. Chronic administration of efavirenz may adversely affect the auditory system by affecting the microanatomy of the inferior colliculus of adult Wistar rats.

Darunavir/ritonavir and efavirenz exert differential effects on MRP1 transporter expression and function in healthy volunteers

The efflux transporter MRP1 actively transports antiretrovirals and reduces intracellular accumulation in peripheral blood mononuclear cells (PBMCs). We studied MRP1 expression and function in healthy volunteers treated with darunavir/ritonavir and efavirenz. Seven healthy HIV-negative volunteers were recruited. PBMCs were collected at baseline, 9 days after administration of darunavir (900 mg) and ritonavir (100 mg) once daily, 9 days after coadministration of darunavir/ritonavir and efavirenz (600 mg) once daily and 13 days after administration of efavirenz alone. MRP1 expression was measured in PBMCs using flow cytometry with fluorescein isothiocyanate-conjugated antibody against MRP1m6. MRP1 expression was also measured in CD4(+) T-cells with a phycoerythrin-conjugated antibody against CD4. MRP1 efflux function was assessed by incubating PBMCs with carboxyfluorescein diacetate (CFDA) and comparing CFDA fluorescence with and without the modulators MK571 and probenecid. MRP1 expression was reduced after darunavir/ritonavir administration (geometric mean ratio [GMR] 0.58, 95% confidence interval [95% CI] 0.51-0.65; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 0.74, 95% CI 0.64-0.84; P=0.001), but not after efavirenz administration alone (GMR 0.82, 95% CI 0.64-1.06; P=0.10). MRP1 protein expression was 41% higher in CD4(+) T-cells. MRP1 efflux function was increased after efavirenz administration (GMR 3.13, 95% CI 2.73-3.59; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 4.35, 95% CI 3.35-5.68; P<0.001), but not after darunavir/ritonavir administration (GMR 1.06, 95% CI 0.80-1.42; P=0.42). Darunavir/ritonavir and efavirenz treatment exerted differential effects on MRP1 expression and function. These effects could potentially alter antiviral activity, especially in CD4(+) T-cells.

Histological effects of chronic administration of efavirenz on lateral geniculate body of adult Wistar rats.

Background:The effects of chronic administration of efavirenz commonly used as part of highly active antiretroviral therapy (HAART) for the treatment of Human Immunodeficiency Virus (HIV) type-1 on the weight of the brain and inferior colliculus of adult Wistar rats was carefully studied.Methods and MaterialsThe rats of both sexes (n = 24), with average weight of 200g were randomly assigned into two treatment (A & B) (n=16) and Control (c) (n=8) groups. The rats in the treatment group received 600mg/70kg bogy weight of efavirenz dissolved in distilled water daily for 30days through the orogastric tube. The control group received equal volume of distilled through the same route. All rats were fed with grower's mash and given water liberally. The rats were sacrificed by cervical dislocation method on the thirty-first day of the experiment and the lateral geniculate body was carefully dissected out and quickly fixed in 10% formal saline for histological study.ResultsThe findings indicate that rats in the treated group showed some cellular degenerative changes like sparse cellular population, pyknotic nuclei with some microcystic changes and edema in the stroma of the lateral geniculate body as compared to the control group.ConclusionChronic administration of efavirenz may have an adverse effect on the visual sensibilities by affecting the microanatomy of the lateral geniculate body of adult Wistar rats. It is recommended that further studies aimed at corroborating these observations be carried out.