Efavirenz (Page 5 of 10)

11 DESCRIPTION

Efavirenz is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz USP is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C14 H9 ClF3 NO2 and its structural formula is:

Efavirenzstructure


Efavirenz USP is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (<10 microgram/mL).Tablets: Efavirenz are available as film-coated tablets for oral administration containing 600 mg of efavirenz USP and the following inactive ingredients: microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate. The film coating contains Opadry® Yellow (hypromellose, titanium dioxide, iron oxide yellow and polyethylene glycol).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Efavirenz is an antiviral drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions (5.2)].

12.3 Pharmacokinetics

Absorption
Peak efavirenz plasma concentrations of 1.6 to 9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1,600 mg; the increases were less than proportional suggesting diminished absorption at higher doses.
In HIV-1-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 to 5 hours and steady-state plasma concentrations were reached in 6 to 10 days. In 35 patients receiving efavirenz tablets 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:
Tablets: Administration of a single 600 mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1,000 kcal, 500 to 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 (2) and Patient Counseling Information (17.]
Distribution
Efavirenz is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz tablets 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 CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism.
Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200 to 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22 to 42% lower) and a shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours).
Elimination
Efavirenz has a terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14 C-labeled dose administered on Day 8. Approximately 14 to 34% of the radiolabel was recovered in the urine and 16 to 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
Pediatric: The pharmacokinetic parameters for efavirenz at steady state in pediatric patients were predicted by a population pharmacokinetic model.
Gender and race: The pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied.
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.
Hepatic impairment: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics.
Drug Interaction Studies
Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9 and 2C19 with Ki values (8.5 to 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 to 160 μM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 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 7 (effect of efavirenz on other drugs) and Table 8 (effect of other drugs on efavirenz). For information regarding clinical recommendations see Drug Interactions (7.1).

Table 7: Effect of Efavirenz on Coadministered Drug Plasma Cmax , AUC, and Cmin

↑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 in this study were 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 insufficient data. NA = not available.
Coadministered Drug Dose Efavirenz Dose Number of Subjects Coadministered Drug (mean % change)
Cmax (90% CI) AUC (90% CI) Cmin (90%CI)
Atazanavir 400 mg qd with a light meal d 1-20400 mg qd d 1-6, then 300 mg qd d 7-20 with ritonavir 100 mg qd and a light meal300 mg qd/ritonavir 100 mg qd d 1-10 (pm), then 400 mg qd d 11-24 (pm) (simultaneous with efavirenz) 600 mg qd qd with a light meal d 7-20600 mg qd 2 h after atazanavir and ritonavir d 7-20600 mg qd withn a light snack d 11-24 (pm) 271314 ↓59% (49-67%)↑ 14%a (↓17- ↑58%)↑17% (8-27%) ↓74% (68-78%)↑39%a (2-88%)↔ ↓93% (90-95%)↑48%a (24-76%)↓42% (31-51%)
Indinavir 1000 mg q8hx 10 daysAfter morningDoseAfter afternoondoseAfter eveningdose 600 mg qd ×10 days 20 bb ↓ 29%b (11-43%) ↓33%b (26-39%)↓ 37%b (26-46%)↓ 46%b (37-54%) ↓ 39%b (24-51%)↓52%b (47-57%)↓ 57%b (50-63%)
Lopinavir/ritonavir 400/ 100 mgCapsules q 12 x 9days500/ 125 mg tabletq 12 x 10 dayswith efavirenzcompared to400/100 mg q 12 hAlone600/150 mg tabletQ 12 x 10 dayswith efavirenzcompared to400/100 mg q 12 halone 600 mg qd x9 days600 mg qd x9 days600 mg qd x9 days 11,7c 1923 d ↑ 12%d (2-23%)↑ 36%d (28-44%) ↓ 19%d (↓ 36-↑ 3%)↔d 36%d (28-44%) ↓ 39%d (3-62%)↓ 10%d ( ↓ 22-↑ 4 %)↑ 32%d (21-44%)
NelfinavirMetaboliteAG-1402 750 mg q8h x 7days 600 mg qd x7 days 10 ↑ 21%(10-33)↓ 40%(30-48) ↑ 20%(8-34%)↓ 37%(25-48%) ↔↓ 43%(21-59%)
Ritonavir 500 mg q 12 × 8daysAfter AM doseAfter PM dose 600 mg qd x10 days 11 ↑ 24%(12-38%)↔ ↑ 18%(6-33%)↔ ↑ 42%(9-86%)e ↑ 24%( 3-50)e
SaquinavirSGCf 1200 mg q8hX 10 days 600 mg qd x10 days 12 ↓ 50%(28-66%) ↓ 62%(45-74%) ↓ 56%(16-77%)e
Lamivudine 150 mg q 12 hx 14 days 60014 days 9 ↑ 265%(37-873%)
Tenofovirg 300 mg qd 600 mg qd x14 days 29
zidovudine 300 mg q 12h 600 mg qd x14 days 9 ↑ 225%(43-640%)
Maraviroc 100 mg bid 600 mg qd 12 ↓ 51% (37-62%) ↓ 45%(38-51%) ↓ 45%(28-57%)
Raltegravir 400 mg singledose 600 mg qd 9 ↓ 36%(2-59) ↓ 36%(20-48%) ↓ 21%( ↓ 51-↑ 28%)
Boceprevir 800 mg tid x 6days 600 mg qd x16 days NA ↓ 8%(↓ 22-↑ 8%) ↓19%(11-25%) ↓ 44%(26-58%)
Simeprevir 150 mg qd x 14days 600 mg qd x14 days 23 ↓ 51%(↓46-↓ 56%) ↓71%(↓ 67-↓74% ↓ 91%(↓88%-↓92%
Azithromycin 600 mg singledose 400 mg qd x7 days 14 ↑ 22%(4-42%) NA
Clarithromycin14-OHmetabolite 500 mg q12hX 7 days 400 mg qd x7 days 11 ↓ 26%(15-35%)↑ 49%(32-69%) ↓ 39%(30-46%)↑ 34%(18-53%) ↓ 53%(42-63%)↑ 26%(9-45%)
Fluconazole 200 mg x7 days 400 mg qd x7 days 10
ItraconazoleHydroxyl-itraconazole 200 mg q 12h x28 days 600 mg qd x14 days 18 ↓ 37%(20-51%)↓ 35%(12-52%) ↓ 39%(21-53%)↓ 37%(14-55%) ↓ 44%(27-58%)↓ 43%(18-60%)
Posaconazole 400 mg (oralSuspension) bid x10 and 20 days 400 mg qd x10 and 20days 11 ↓45%(34-53%) ↓ 50%(40-57%) NA
Rifabutin 300 mg qd x14 days 600 mg qd +X14 days 9 ↓ 32%(15-46%) ↓ 38%(28-47%) ↓ 45%(31-56%)
Voriconazole 400 mg po q 12h x1 day, then 200 mgPo q 12h x8 days300 mg po q 12hDays 2-7400 mg po q 12hdays 2-7 400 mg qd x9 days300 mg qd x7 days300 mg qd x7 days NANANA ↓ 61%h36%i (21-49%)↑ 23%i (↓ 1 –↑53%) ↓ 77%h ↓ 55%i (45-62%)↓ 7%i (↓23 -↑ 13%) NANANA
Artemether/lumefantrineArthemetherdihydroartemisininlamefantrine Artemether20 mg /lumefantrine 120 mg tablets (6 4- tablet doses over 3 days) 600 mg qd x 26 days 12 ↓ 21%↓ 38%↔ ↓ 51%↓ 46%↓ 21% NANANA
AtorvastatinTotal active(includingmetabolites 10 mg qd x4 days 600 mg qd x15 days 14 ↓ 14%(1-26%)↓ 15%(2-26%) ↓ 43%(34-50%)↓ 32%(21-41%) ↓ 69%(49-81%)↓ 48%(23-64%)
pravastatin 40 mg qd x4 days 600 mg qd x15 days 13 ↓ 32%(↓ 59-↑ 12%) ↓ 44%(26-57%) ↓ 19%(0-35%)
SimavastatinTotal active(includingMetabolites) 40 mg qd x4 days 600 mg qd x15 days 14 ↓ 72%(63-79%)↓ 68 %(55-78 %) ↓ 68%(62-73%)↓ 60 %(52-68 %) ↓ 45%(20-62%)NAj
CarbamazepineEpoxidemetabolite 200 mg qd x 3 days,200 mg bid x3 days, then 400 mgqd x 29 days 600 mg qd x14 days 12 ↓ 20%(15-24%)↔ ↓ 27%(20-33%)↔ ↓ 35%(24-44%)↓ 13%(↓ 30-↑7%)
Cetirizine 10 mg single dose 600 mg qd x10 days 11 ↓24%(18-30%) NA
DiltiazemDesacetyldiltiazemN- monodes-Methyl diltiazem 240 mg x 21 days 600 mg qd x14 days 13 ↓ 60%(50-68%)↓ 64%(57-69%)↓ 28%(7-44%) ↓ 69%(55-79%)↓ 75%(59-84%)↓ 37%(17-52%) ↓63%(44-75%)↓ 62%(44-75%)↓ 37%(17-52%)
Ethinyl estradiol/NorgestimateEthinylestradiolNorelgestrominLevonorgestrel 0.035 mg/0.25 mg x14 days 600 mg qd x14 days 21216 ↔↓ 46%(39-52%)↓ 80%(77-83%) ↔↓ 64%(62-67%)↓ 83%(79-87%) ↔↓ 82%(79-85%)↓ 86%(80-90%)
Lorazepam 2 mg single dose 600 mg qd x10 days 12 ↑ 16%(2-32%) NA
Methadone Stable maintenance35-100 mg daily 600 mg qd x14-21 days 11 ↓ 45%(25-59%) ↓ 52%(33-66%) NA
BupropionHydroxyl-bupropion 150 mg single dose(sustained-release) 600 mg qd x14 days 13 ↓ 34%(21-47%)↑ 50%(20-80%) ↓ 55%(48-62%)↔ NANA
Paroxetine 20 mg qd x 14 days 600 mg qd x14 days 16
Sertraline 50 mg qd x 14 days 600 mg qd x14 days 13 ↓ 29%(15-40%) ↓ 39%(27-50%) ↓ 46%(31-58%)

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