Protein-Free Efavirenz Concentrations in Cerebrospinal Fluid and Blood Plasma Are Equivalent: Applying the Law of Mass Action To Predict Protein-Free Drug Concentration

Avery, L. B.; Sacktor, Ned; McArthur, Justin C.; Hendrix, Craig W.

doi:10.1128/aac.02329-12

Cited by 41 publications

(31 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In plasma, efavirenz is highly protein bound (f u ϭ 0.01) (24). Protein binding in the CSF is much lower, leading to more free efavirenz (f u ϭ 0.238) (21). The data presented here for rapid equilibrium dialysis show the efavirenz f u in rodent brain tissue to be 0.00197.…”

Section: Discussionmentioning

confidence: 61%

“…If the last efavirenz dose was administered, for example, 3 days prior to death, then the brain tissue concentrations may not accurately reflect those that occur in living, adherent patients. However, efavirenz has been shown to display a long plasma half-life (40 to 52 h) (21). This indicates that patients would have ceased receiving efavirenz for many days or had poor adherence in order to explain the very low concentrations observed.…”

Section: Discussionmentioning

confidence: 87%

See 1 more Smart Citation

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Curley

Rajoli

Moss

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight Ϫ1 ) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/ MS). The median maximum concentrations of drug (C max ) were predicted to be 3,184 ng ml Ϫ1 (interquartile range [IQR], 2,219 to 4,851 ng ml Ϫ1 ), 49.9 ng ml Ϫ1 (IQR, 36.6 to 69.7 ng ml Ϫ1 ), and 50,343 ng ml Ϫ1 (IQR, 38,351 to 65,799 ng ml Ϫ1 ) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg Ϫ1 ), the median plasma and brain tissue concentrations in rats were 69.7 ng ml Ϫ1 (IQR, 44.9 to 130.6 ng ml Ϫ1 ) and 702.9 ng ml Ϫ1 (IQR, 475.5 to 1,018.0 ng ml Ϫ1 ), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution.

show abstract

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 87%

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Curley

Rajoli

Moss

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…In addition to FM, another determinant of variability in the apparent V of efavirenz may be the interaction with plasma proteins. Efavirenz is estimated to be Ͼ99% bound to serum albumin, and inter-and intrasubject variability in albumin may contribute to variability in V/F by modifying plasma/tissue partition (14). Mechanistically, as only free drug is available to diffuse across the membranes and would be available to be enzymatically degraded by the liver, variability in free plasma concentrations may also be an important determinant to variability in efavirenz clearance that is not explained by between-subject differences in enzymatic clearance due to genetic polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6. While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported. The aim of this analysis was to develop a pharmacometric model to quantify the contribution of genetic and nongenetic factors to efavirenz pharmacokinetics. A population-based pharmacokinetic model was developed using 1,132 plasma efavirenz concentrations obtained from 73 HIV-seronegative volunteers administered a single oral dose of 600 mg efavirenz. A two-compartment structural model with absorption occurring by zero-and firstorder processes described the data. Allometric scaling adequately described the relationship between fat-free mass and apparent oral clearance, as well as fat mass and apparent peripheral volume of distribution. Inclusion of fat-free mass and fat mass in the model mechanistically accounted for correlation between these disposition parameters and sex, weight, and body mass index. Apparent oral clearance of efavirenz was reduced by 25% and 51% in subjects predicted to have intermediate and slow CYP2B6 metabolizer status, respectively. The final pharmacokinetic model accounting for fat-free mass, fat mass, and CYP2B6 metabolizer status was consistent with known mechanisms of efavirenz disposition, efavirenz physiochemical properties, and pharmacokinetic theory. (This study has been registered at ClinicalTrials.gov under identifier NCT00668395.) KEYWORDS body composition, cytochrome P450 2B6 (CYP2B6), efavirenz, population pharmacokinetics E favirenz is a nonnucleoside reverse transcriptase inhibitor that is used in combination with nucleoside/nucleotide reverse transcriptase inhibitors to treat HIVinfected individuals older than 3 years who are naive to antiretroviral drugs. Due to its proven efficacy and low cost relative to newer antiretrovirals, efavirenz-based therapy remains the preferred first-line regimen in many low-income nations and is consequently one of the most commonly prescribed antiretroviral drugs (1). Efavirenz pharmacokinetics (PK) is characterized by large interindividual variability in plasma concentrations following a single dose (2, 3) and during chronic administration (4), which has important clinical implications. During the induction phase, efavirenz exposure is associated with central nervous system and psychiatric adverse events, liver enzyme elevation, and rash, among others (5, 6). This may result in increasing rates of

show abstract

“…Efavirenz has a very high tendency to bind proteins (e.g, approximately 99.8% is bound to plasma proteins) [14, 15], and healthy CSF contains very little protein compared to that in blood plasma (< 1%). Since the concentration of free efavirenz in the aqueous fraction is expected to be low and it binds to protein-rich brain tissue [16], one might expect that 44 nM in CSF, if it accounted for approximately 0.2% (100%−99.8%) of the efavirenz dose, would correspond to an estimated 22 μM (44 nM ÷ 0.002) concentration of efavirenz in brain tissue.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz

Dalwadi

Kim

Chen

et al. 2016

Pharmacological Research

View full text Add to dashboard Cite

Efavirenz is highly effective at suppressing HIV-1, and the WHO guidelines list it as a component of the first-line antiretroviral (ARV) therapies for treatment-naïve patients. Though the pharmacological basis is unclear, efavirenz is commonly associated with a risk for neuropsychiatric adverse events (NPAEs) when taken at the prescribed dose. In many patients these NPAEs appear to subside after several weeks of treatment, though long-term studies show that in some patients the NPAEs persist. In a recent study focusing on the abuse potential of efavirenz, its receptor psychopharmacology was reported to include interactions with a number of established molecular targets for known drugs of abuse, and it displayed a prevailing behavioral profile in rodents resembling an LSD-like activity. In this report, we discovered interactions with additional serotonergic targets that may be associated with efavirenz-induced NPAEs. The most robust interactions were with 5-HT3A and 5-HT6 receptors, with more modest interactions noted for the 5-HT2B receptor and monoamine oxidase A. From a molecular mechanistic perspective, efavirenz acts as a 5-HT6 receptor inverse agonist of Gs-signaling, 5-HT2A and 5-HT2C antagonist of Gq-signaling, and a blocker of the 5-HT3A receptor currents. Efavirenz also completely or partially blocks agonist stimulation of the M1 and M3 muscarinic receptors, respectively. Schild analysis suggests that efavirenz competes for the same site on the 5-HT2A receptor as two known hallucinogenic partial agonists (±)-DOI and LSD. Prolonged exposure to efavirenz reduces 5-HT2A receptor density and responsiveness to 5-HT. Other ARVs such as zidovudine, nevirapine and emtricitabine did not share the same complex pharmacological profile as efavirenz, though some of them weakly interact with the 5-HT6 receptor or modestly block GABAA currents.

show abstract

Protein-Free Efavirenz Concentrations in Cerebrospinal Fluid and Blood Plasma Are Equivalent: Applying the Law of Mass Action To Predict Protein-Free Drug Concentration

Cited by 41 publications

References 34 publications

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz

Contact Info

Product

Resources

About