CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption: Peak efavirenz plasma concentrations of 1.6-9.1 µM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses.
In HIV-infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were dose proportional following 200-mg, 400-mg, and 600-mg daily doses. Time-to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving SUSTIVA 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 µM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 µM, and AUC was 184 ± 73 µM•h.
Effect of Food on Oral Absorption:
Capsules —Administration of a single 600-mg dose of efavirenz capsules with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS: Information for Patients.)
Tablets —Administration of a single 600-mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS: Information for Patients.)
Distribution: Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received SUSTIVA 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.
Metabolism: Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism.
Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours).
Elimination: Efavirenz has a terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14C labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.
Special Populations
Hepatic Impairment: The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic impairment (see PRECAUTIONS: General).
Renal Impairment: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
Gender and Race: The pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied.
Geriatric: see PRECAUTIONS: Geriatric Use
Pediatrics: see PRECAUTIONS: Pediatric Use
Drug Interactions (see also CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions)
Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A4. In vitro studies have shown that efavirenz inhibited P450 isozymes 2C9, 2C19, and 3A4 with Ki values (8.5-17 µM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82-160 µM) only at concentrations well above those achieved clinically. The effects on CYP3A4 activity are expected to be similar between 200-mg, 400-mg, and 600-mg doses of efavirenz. Coadministration of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A4 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A4 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.
Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of efavirenz on the Cmax, AUC, and Cmin are summarized in Table 1 (effect of efavirenz on other drugs) and Table 2 (effect of other drugs on efavirenz). For information regarding clinical recommendations see PRECAUTIONS: Drug Interactions.
Table 1: Effect of Efavirenz on Coadministered Drug Plasma Cmax, AUC, and Cmin | Coadministered Drug
(mean % change) |
Coadministered
Drug |
Dose |
Efavirenz Dose |
Number
of
Subjects | Cmax
(90% CI) | AUC
(90% CI) | Cmin
(90%CI) |
| ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. |
| a Compared with atazanavir 400 mg qd alone. |
| b Comparator dose of indinavir was 800 mg q8h x 10 days. |
| c Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for lopinavir/ritonavir alone. |
| d Values are for lopinavir; the pharmacokinetics of ritonavir are unaffected by concurrent efavirenz. |
| e 95% CI. |
| f Soft Gelatin Capsule. |
| g Tenofovir disoproxil fumarate. |
| h 90% CI not available. |
| i Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). |
| j Not available because of insufficent data. |
| NA = not available. |
| Atazanavir | 400 mg qd with a light meal d 1-20 | 600 mg qd with a light meal d 7-20 | 27 | ↓59%
(49-67%) | ↓74%
(68-78%) | ↓ 93%
(90-95%) |
| 400 mg qd d 1-6, then 300 mg qd d 7-20 with ritonavir 100 mg qd and a light meal | 600 mg qd 2 h after atazanavir and ritonavir d 7-20 | 13 | ↑14%a
(↓17-↑58%) | ↑39%a
(2-88%) | ↑ 48%a
(24-76%) |
| Indinavir | 1000 mg q8h x 10 days | 600 mg x 10 days | 20 | |
| After morning dose | ↔b | ↓33%b
(26-39%) | ↓39%b
(24-51%) |
| After afternoon dose | ↔b | ↓37%b
(26-46%) | ↓52% b
(47-57%) |
| After evening dose | ↓29%b
(11-43%) | ↓46%b
(37-54%) | ↓57%b
(50-63%) |
Lopinavir/
ritonavir | 400/100 mg capsule
q12h x 9 days | 600 mg x 9 days | 11,7c | ↔d | ↓19%d
(↓ 36-↑ 3%) | ↓39%d
(3-62%) |
| | 600/150 mg tablet
q12h x 10 days with
efavirenz compared to
400/100 mg q12h alone | 600 mg x 9 days | 23 | ↑36%d
(28-44%) | ↑36%d
(28-44%) | ↑32%d
(21-44%) |
| Nelfinavir | 750 mg q8h x 7 days | 600 mg x 7 days | 10 | ↑21%
(10-33%) | ↑20%
(8-34%) | ↔ |
Metabolite
AG-1402 | | ↓40%
(30-48%) | ↓37%
(25-48%) | ↓43%
(21-59%) |
| Ritonavir | 500 mg q12h x 8 days | 600 mg x 10 days | 11 | |
| After AM dose | | ↑24%
(12-38%) | ↑18%
(6-33%) | ↑42%
(9-86%)e |
| After PM dose | | ↔ | ↔ | ↑24%
(3-50%)e |
Saquinavir
SGCf | 1200 mg q8h x 10 days | 600 mg x 10 days | 12 | ↓50%
(28-66%) | ↓62%
(45-74%) | ↓56%
(16-77%)e |
| Lamivudine | 150 mg q12h x 14 days | 600 mg x 14 days | 9 | ↔ | ↔ | ↑265%
(37-873%) |
| Tenofovirg | 300 mg qd | 600 mg x 14 days | 29 | ↔ | ↔ | ↔ |
| Zidovudine | 300 mg q12h x 14 days | 600 mg x 14 days | 9 | ↔ | ↔ | ↑ 225%
(43-640%) |
| Azithromycin | 600 mg single dose | 400 mg x 7 days | 14 | ↑22%
(4-42%) | ↔ | NA |
| Clarithromycin | 500 mg q12h x 7 days | 400 mg x 7 days | 11 | ↓26%
(15-35%) | ↓39%
(30-46%) | ↓53%
(42-63%) |
| 14-OH metabolite | | ↑49%
(32-69%) | ↑34%
(18-53%) | ↑26%
(9-45%) |
| Fluconazole | 200 mg x 7 days | 400 mg x 7 days | 10 | ↔ | ↔ | ↔ |
| Itraconazole | 200 mg q12h x 28 days | 600 mg x 14 days | 18 | ↓ 37%
(20-51%) | ↓ 39%
(21-53%) | ↓ 44%
(27-58%) |
| Hydroxyitraconazole | | ↓ 35%
(12-52%) | ↓ 37%
(14-55%) | ↓ 43%
(18-60%) |
| Rifabutin | 300 mg qd x 14 days | 600 mg x 14 days | 9 | ↓ 32%
(15-46%) | ↓ 38%
(28-47%) | ↓ 45%
(31-56%) |
| Voriconazole | 400 mg po q12h x 1 day then 200 mg po q12h x 8 days | 400 mg x 9 days | NA | ↓ 61%h | ↓ 77%h | NA |
| 300 mg po q12h days 2-7 | 300 mg x 7 days | NA | ↓ 36%i
(21-49%) | ↓55%i
(45-62%) | NA |
| 400 mg po q12h days 2-7 | 300 mg x 7 days | NA | ↑ 23%i
(↓ 1-↑ 53%) | ↓ 7%i
(↓ 23-↑ 13%) | NA |
| Atorvastatin | 10 mg qd x 4 days | 600 mg x 15 days | 14 | ↓ 14%
(1-26%) | ↓ 43%
(34-50%) | ↓ 69%
(49-81%) |
Total active (including
metabolites) | | ↓ 15%
(2-26%) | ↓ 32%
(21-41%) | ↓ 48%
(23-64%) |
| Pravastatin | 40 mg qd x 4 days | 600 mg x 15 days | 13 | ↓ 32%
(↓ 59-↑ 12%) | ↓ 44%
(26-57%) | ↓ 19%
(0-35%) |
| Simvastatin | 40 mg qd x 4 days | 600 mg x 15 days | 14 | ↓ 72%
(63-79%) | ↓ 68%
(62-73%) | ↓ 45%
(20-62%) |
Total active (including
metabolites) | | ↓ 68%
(55-78%) | ↓ 60%
(52-68%) | NAj |
| Carbamazepine | 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 29 days | 600 mg x 14 days | 12 | ↓20%
(15-24%) | ↓27%
(20-33%) | ↓35%
(24-44%) |
| Epoxide metabolite | | ↔ | ↔ | ↓13%
(↓30-↑7%) |
| Cetirizine | 10 mg single dose | 600 mg x 10 days | 11 | ↓24%
(18-30%) | ↔ | NA |
| Diltiazem | 240 mg x 21 days | 600 mg x 14 days | 13 | ↓ 60%
(50-68%) | ↓ 69%
(55-79%) | ↓ 63%
(44-75%) |
| Desacetyl diltiazem | | ↓ 64%
(57-69%) | ↓ 75%
(59-84%) | ↓ 62%
(44-75%) |
N-monodesmethyl
diltiazem | | ↓ 28%
(7-44%) | ↓ 37%
(17-52%) | ↓ 37%
(17-52%) |
| Ethinyl estradiol | 50 µg single dose | 400 mg x 10 days | 13 | ↔ | ↑37%
(25-51%) | NA |
| Lorazepam | 2 mg single dose | 600 mg x 10 days | 12 | ↑16%
(2-32%) | ↔ | NA |
| Methadone | Stable
maintenance 35-
100 mg daily | 600 mg x 14-21 days | 11 | ↓45%
(25-59%) | ↓52%
(33-66%) | NA |
| Paroxetine | 20 mg qd x 14 days | 600 mg x 14 days | 16 | ↔ | ↔ | ↔ |
| Sertraline | 50 mg qd x 14 days | 600 mg x 14 days | 13 | ↓29%
(15-40%) | ↓39%
(27-50%) | ↓ 46%
(31-58%) |
Table 2: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin | Efavirenz
(mean % change) |
Coadministered
Drug |
Dose |
Efavirenz Dose |
Number
of
Subjects | Cmax
(90% CI) | AUC
(90% CI) | Cmin
(90%CI) |
| ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. |
| a Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for efavirenz alone. |
| b 95% CI. |
| c Soft Gelatin Capsule. |
| d Tenofovir disoproxil fumarate. |
| e 90% CI not available. |
| f Relative to steady-state administration of efavirenz (600 mg once daily for 9 days). |
| NA = not available. |
| Indinavir | 800 mg q8h x 14 days | 200 mg x 14 days | 11 | ↔ | ↔ | ↔ |
Lopinavir/
ritonavir | 400/100 mg q12h x 9 days | 600 mg x 9 days | 11,12a | ↔ | ↓16%
(↓38-↑15%) | ↓16%
(↓42-↑20%) |
| Nelfinavir | 750 mg q8h x 7 days | 600 mg x 7 days | 10 | ↓12%
(↓32-↑13%)b | ↓12%
(↓35-↑18%)b | ↓21%
(↓53-↑33%) |
| Ritonavir | 500 mg q12h x 8 days | 600 mg x 10 days | 9 | ↑14%
(4-26%) | ↑21%
(10-34%) | ↑25%
(7-46%)b |
Saquinavir
SGCc | 1200 mg q8h x 10 days | 600 mg x 10 days | 13 | ↓13%
(5-20%) | ↓12%
(4-19%) | ↓14%
(2-24%)b |
| Tenofovird | 300 mg qd | 600 mg x 14 days | 30 | ↔ | ↔ | ↔ |
| Azithromycin | 600 mg single dose | 400 mg x 7 days | 14 | ↔ | ↔ | ↔ |
| Clarithromycin | 500 mg q12h x 7 days | 400 mg x 7 days | 12 | ↑11%
(3-19%) | ↔ | ↔ |
| Fluconazole | 200 mg x 7 days | 400 mg x 7 days | 10 | ↔ | ↑16%
(6-26%) | ↑22%
(5-41%) |
| Itraconazole | 200 mg q12h x 14 days | 600 mg x 28 days | 16 | ↔ | ↔ | ↔ |
| Rifabutin | 300 mg qd x 14 days | 600 mg x 14 days | 11 | ↔ | ↔ | ↓12%
(↓24-↑1%) |
| Rifampin | 600 mg x 7 days | 600 mg x 7 days | 12 | ↓20%
(11-28%) | ↓26%
(15-36%) | ↓32%
(15-46%) |
| Voriconazole | 400 mg po q12h x 1 day then 200 mg po q12h x 8 days | 400 mg x 9 days | NA | ↑38%e | ↑44%e | NA |
| | 300 mg po q12h days 2-7 | 300 mg x 7 days | NA | ↓ 14%f
(7-21%) | ↔f
| NA |
| | 400 mg po q12h days 2-7 | 300 mg x 7 days | NA | ↔f | ↑ 17%f
(6-29%) | NA |
| Atorvastatin | 10 mg qd x 4 days | 600 mg x 15 days | 14 | ↔ | ↔ | ↔ |
| Pravastatin | 40 mg qd x 4 days | 600 mg x 15 days | 11 | ↔ | ↔ | ↔ |
| Simvastatin | 40 mg qd x 4 days | 600 mg x 15 days | 14 | ↓ 12%
(↓ 28-↑ 8%) | ↔ | ↓ 12%
(↓ 25-↑ 3%) |
Aluminum
hydroxide
400 mg,
magnesium
hydroxide
400 mg, plus
simethicone
40 mg | 30 mL single dose | 400 mg single dose | 17 | ↔ | ↔ | NA |
| Carbamazepine | 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 15 days | 600 mg x 35 days | 14 | ↓21%
(15-26%) | ↓36%
(32-40%) | ↓47%
(41-53%) |
| Cetirizine | 10 mg single dose | 600 mg x 10 days | 11 | ↔ | ↔ | ↔ |
| Diltiazem | 240 mg x 14 days | 600 mg x 28 days | 12 | ↑ 16%
(6-26%) | ↑ 11%
(5-18%) | ↑ 13%
(1-26%) |
| Ethinyl estradiol | 50 µg single dose | 400 mg x 10 days | 13 | ↔ | ↔ | ↔ |
| Famotidine | 40 mg single dose | 400 mg single dose | 17 | ↔ | ↔ | NA |
| Paroxetine | 20 mg qd x 14 days | 600 mg x 14 days | 12 | ↔ | ↔ | ↔ |
| Sertraline | 50 mg qd x 14 days | 600 mg x 14 days | 13 | ↑11%
(6-16%) | ↔ | ↔ |
|
