Are Literature References Sufficient for Dose Recommendations? An FDA Case Study of Efavirenz and Rifampin

DiGiacinto, Jennifer L.; Chan-Tack, Kirk M.; Robertson, Sarah; Reynolds, Kellie S.; Struble, Kimberly

doi:10.1177/0091270008315308

Cited by 11 publications

(10 citation statements)

References 20 publications

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“…The simulated effects of rifampicin co-administration on efavirenz treatment showed only a minor decrease of 16% (95% confidence interval [13][14][15][16][17][18][19] in efavirenz area under the concentration-time curve, of the same magnitude as what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight.…”

Section: Resultsmentioning

confidence: 99%

“…Efavirenz steady-state oral efavirenz clearance was estimated as 12.6 l h -1 with concomitant rifampicin, which is somewhat lower than clinical data (17.2 l h -1 ). The simulations of continuous efavirenz administration predicted a mean decrease in efavirenz AUC of 16% [95% confidence interval (CI) [13][14][15][16][17][18][19] in the presence of rifampicin.The model predicted mean decreases in Cmax and Ctrough of 14 (95% CI 11-16) and 18% (95% CI 15-21), respectively.…”

Section: Figurementioning

confidence: 99%

“…The Centers for Disease Control and Prevention (CDC) have in their 2007 guide suggested that a 22% decrease of efavirenz exposure is unlikely to be of any clinical meaning [19]. However, in a recent food and drug administration case study, it is argued that suboptimal drug concentrations can lead to virological failure, and further clinical trials or in silico simulations are encouraged [17].…”

Section: Introductionmentioning

confidence: 99%

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In silico prediction of efavirenz and rifampicin drug–drug interaction considering weight and CYP2B6 phenotype

Rekić

Röshammar

Mukonzo

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rifampicin is known to reduce the exposure of efavirenz. Despite lack of adequate clinical support, most guidelines recommend an increased efavirenz dose in patients treated with both drugs, although some propose an increase only in patients weighing over 50 kg. WHAT THIS STUDY ADDS • An example of utilization of in vitro data to predict in vivo consequences of metabolic drug–drug interactions, suggesting answers to specific questions difficult to study in patients. Here the efavirenz–rifampicin interaction was simulated with the specific question of whether or not to increase the efavirenz dose based on bodyweight. • The results from this simulation suggest that increasing the efavirenz dose may be appropriate only in patients with bodyweights over 50 kg. AIMS This study aimed to test whether a pharmacokinetic simulation model could extrapolate nonclinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight‐based dosage recommendations used to counteract the rifampicin–efavirenz interaction. METHODS Efavirenz pharmacokinetics were simulated using a physiologically based pharmacokinetic model implemented in the Simcyp™ population‐based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype. RESULTS Apart from the absorption phase, the simulation model predicted efavirenz concentration–time profiles reasonably well, with close agreement with clinical data. The simulated effects of rifampicin co‐administration on efavirenz treatment showed only a minor decrease of 16% (95% confidence interval 13–19) in efavirenz area under the concentration–time curve, of the same magnitude as what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status. CONCLUSIONS Our findings, although based on a simulation approach using limited in vitro data, support the current recommendations for using a 50 kg bodyweight cut‐off for efavirenz dose increment when co‐treating with rifampicin.

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Section: Resultsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In silico prediction of efavirenz and rifampicin drug–drug interaction considering weight and CYP2B6 phenotype

Rekić

Röshammar

Mukonzo

et al. 2011

Brit J Clinical Pharma

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“…An extensive review of published literature did not find adequate evidence to support a dose increase with rifampin coadministration because of current lack of understanding of the likelihood of under-or overdosing individuals (11). Prior drug-drug interaction studies failed to evaluate genetic contributions to the variability in the induction effect of rifampin (2,24), were performed in the setting of clinical care, where patients were receiving other antituberculous drugs in addition to rifampin, or did not have an appropriate control period or comparator group (13,20,25,35).…”

mentioning

confidence: 99%

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

Kwara

Tashima

Dumond

et al. 2011

Antimicrob Agents Chemother

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Efavirenz-based antiretroviral regimen is preferred during rifampin-containing tuberculosis therapy. However, current pharmacokinetic data are insufficient to guide optimized concurrent dosing. This study aimed to better characterize the effects of rifampin on efavirenz pharmacokinetics. Subjects were randomized to receive 600 mg efavirenz/day or 600 mg efavirenz with 600 mg rifampin/day for 8 days, with plasma samples collected for pharmacokinetic analysis over 24 h on day 8. Treatments were then crossed over after at least a 2-week washout period, and procedures were repeated. Efavirenz concentrations were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were estimated by noncompartmental analysis. Efavirenz pharmacokinetic differences between treatment periods were evaluated by paired t test. The coefficients of variation in efavirenz plasma AUC 0-24 (area under the concentration-time curve from 0 to 24 h) were 50% and 56% in the absence and presence of rifampin, respectively. Of the 11 evaluable subjects (6 white, 5 black; 6 women, 5 men), the geometric mean AUC 0-24 ratio on/off rifampin (90% confidence interval) was 0.82 (0.72, 0.92), with individual AUC 0-24 ratios varying from 0.55 to 1.18. Five subjects had a 24-hour efavirenz concentration (C 24 ) of <1,000 ng/ml on rifampin. They were more likely to have received a lower dose in milligrams/kilogram of body weight and to have lower efavirenz AUC 0-24 values in the basal state. Although rifampin resulted in a modest reduction in efavirenz plasma exposure in subjects as a whole, there was high variability in responses between subjects, suggesting that efavirenz dose adjustment with rifampin may need to be individualized. Body weight and genetic factors will be important covariates in dosing algorithms.Efavirenz is an essential component of preferred antiretroviral regimens in treatment of human immunodeficiency virus (HIV) infection in patients coinfected with tuberculosis (TB) (6,32,33). The standard adult dose of 600 mg daily is associated with considerable interindividual variability in plasma concentrations and clinical effects (10,28,38). There is even greater variability in efavirenz concentrations during coadministration with rifampin or rifampin-containing TB therapy (2,13,29). Efavirenz is primarily metabolized by hepatic CYP2B6, with some contributions from CYP3A4/5 (42), CYP2A6 (30), and UGT2B7 enzymes (1). Rifampin was shown to be a potent inducer of CYP2B6 activity when bupropion was used as a probe of enzyme activity (22). Among healthy volunteers, rifampin caused 26% and 20% reductions in mean efavirenz area under the curve (AUC) and maximum concentration (C max ), respectively (2). Among HIV-TB-coinfected patients, mean reductions of 24% and 25% in efavirenz AUC and C max , respectively, were reported with rifampin coadministration. In the above-mentioned studies, some subjects had higher efavirenz plasma exposure with rifampin (compared with that when off rifampin), suggesting a lack of a signif...

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“…Although effective pharmacological, clinical, immunological, and virologic responses have been reported with a 600-mg dose of EFV (11,22,27,28), the adequacy of this dose during concomitant treatment with RMP remains a matter of debate. In fact, after reviewing the current literature, the FDA concluded that the available data are insufficient to support definitive dosing recommendations for the coadministration of EFV and RMP (10). Differences in patients' body weights appear to cause further differences in exposure to EFV, raising the question of whether the EFV dose should be increased in people with higher body weights (20,26).…”

mentioning

confidence: 99%

CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India

Ramachandran

Kumar

Rajasekaran

et al. 2009

Antimicrob Agents Chemother

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The dose of efavirenz during concomitant rifampin (RMP) administration is a matter of debate. We studied the influence of RMP coadministration on the steady-state pharmacokinetics of efavirenz in human immunodeficiency virus type 1 (HIV-1)-infected patients in South India. Fifty-seven HIV-tuberculosis (TB)-coinfected and 15 HIV-1-infected patients receiving combination antiretroviral therapy (CART) with an efavirenz (600 mg once daily)-containing regimen were recruited. HIV-TB-coinfected patients were receiving treatment with RMP-containing regimens. A complete pharmacokinetic study was conducted with 19 HIV-TB patients on two occasions (with and without RMP). Trough concentrations of efavirenz were measured in the remaining 38 patients during RMP coadministration. The 15 HIV-infected patients underwent complete pharmacokinetic sampling on one occasion. Plasma efavirenz was estimated by high-performance liquid chromatography, and genotyping of CYP2B6 G516T polymorphism was performed by sequencing. Peak and trough concentrations and exposure to efavirenz were significantly higher in TT than in GT and GG genotype patients (P < 0.001). Although RMP coadministration decreased the peak and trough concentrations and exposure to efavirenz by 17.8, 20.4, and 18.6%, respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 g/ml) in 6 (8%) of 72 patients. In this South Indian population of HIV-infected patients, CYP2B6 G516T polymorphism but not RMP coadministration significantly influenced the pharmacokinetics of efavirenz; patients with the TT genotype had very high blood levels of efavirenz. While a small proportion of patients had subtherapeutic efavirenz levels, the clinical implications are uncertain, as all had good immunological responses to CART.Tuberculosis (TB) remains one of the most important opportunistic infections in human immunodeficiency virus (HIV)-infected individuals. The burden of effectively treating HIV-TB-coinfected patients is a well-recognized global public health problem. A decreased risk of death has been observed in patients starting combination antiretroviral therapy (CART) compared with those not receiving CART after the diagnosis of TB (2, 9, 13). In India, there are effective treatments available for both HIV disease and TB through the government program. Concomitant administration of CART and anti-TB medications is often complicated because of drug-drug interactions and the adverse-effect profile (17,30,36).Efavirenz (EFV) is a potent nonnucleoside reverse transcriptase inhibitor for the treatment of HIV type 1 (HIV-1) infection. EFV has been recommended as a first-line option in antiretroviral therapy (ART) and the preferential choice in TB-and HIV-coinfected patients, despite induction of the cytochrome P-450 system by rifampin (RMP). The available pharmacokinetic data provide evidence of a 13 to 25% reduction in EFV levels when it is coadministered with RMP (20), which is lower than those of nevirapine (40...

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Are Literature References Sufficient for Dose Recommendations? An FDA Case Study of Efavirenz and Rifampin

Cited by 11 publications

References 20 publications

In silico prediction of efavirenz and rifampicin drug–drug interaction considering weight and CYP2B6 phenotype

In silico prediction of efavirenz and rifampicin drug–drug interaction considering weight and CYP2B6 phenotype

Modest but Variable Effect of Rifampin on Steady-State Plasma Pharmacokinetics of Efavirenz in Healthy African-American and Caucasian Volunteers

CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India

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