Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use. Non-nucleoside reverse transcriptase inhibitors. ATC code: J05A G03

Mechanism of action
Efavirenz is a NNRTI of HIV-1. Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases (α, β, γ or δ).

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 section 4.5).

Antiviral activity

The free concentration of efavirenz required for 90 to 95 % inhibition of wild type or zidovudine-resistant laboratory and clinical isolates in vitro ranged from 0.46 to 6.8 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures.

Resistance

The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to that observed against wild type viral strains. The single substitutions which led to the highest resistance to efavirenz in cell culture correspond to a leucine-to-isoleucine change at position 100 (L100I, 17 to 22-fold resistance) and a lysine-to-asparagine at position 103 (K103N, 18 to 33-fold resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing K103N in addition to other amino acid substitutions in RT.

K103N was the most frequently observed RT substitution in viral isolates from patients who experienced a significant rebound in viral load during clinical studies of efavirenz in combination with indinavir or zidovudine + lamivudine. This mutation was observed in 90 % of patients receiving efavirenz with virological failure. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N. The pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of the other antiviral medicinal products used in combination with efavirenz.

Cross resistance

Cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture demonstrated that the K103N substitution confers loss of susceptibility to all three NNRTIs. Two of three delavirdine-resistant clinical isolates examined were cross-resistant to efavirenz and contained the K103N substitution. A third isolate which carried a substitution at position 236 of RT was not cross-resistant to efavirenz.

Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical studies who showed evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteen isolates previously characterised as efavirenz-resistant were also resistant to nevirapine and delavirdine. Five of these NNRTI-resistant isolates were found to have K103N or a valine-to-isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment failure isolates tested remained sensitive to efavirenz in cell culture and were also sensitive to nevirapine and delavirdine.

The potential for cross resistance between efavirenz and PIs is low because of the different enzyme targets involved. The potential for cross-resistance between efavirenz and NRTIs is low because of the different binding sites on the target and mechanism of action.

Clinical efficacy

Efavirenz has not been studied in controlled studies in patients with advanced HIV disease, namely with CD4 counts < 50 cells/mm3, or in PI or NNRTI experienced patients. Clinical experience in controlled studies with combinations including didanosine or zalcitabine is limited.

Two controlled studies (006 and ACTG 364) of approximately one year duration with efavirenz in combination with NRTIs and/or PIs, have demonstrated reduction of viral load below the limit of quantification of the assay and increased CD4 lymphocytes in antiretroviral therapy-naïve and NRTI-experienced HIV-infected patients. Study 020 showed similar activity in NRTI-experienced patients over 24 weeks. In these studies the dose of efavirenz was 600 mg once daily; the dose of indinavir was 1,000 mg every 8 hours when used with efavirenz and 800 mg every 8 hours when used without efavirenz. The dose of nelfinavir was 750 mg given three times a day. The standard doses of NRTIs given every 12 hours were used in each of these studies.

Study 006, a randomized, open-label trial, compared efavirenz + zidovudine + lamivudine or efavirenz + indinavir with indinavir + zidovudine + lamivudine in 1,266 patients who were required to be efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The mean baseline CD4 cell count was 341 cells/mm3 and the mean baseline HIV-RNA level was 60,250 copies/ml. Efficacy results for study 006 on a subset of 614 patients who had been enrolled for at least 48 weeks are found in Table 3.
In the analysis of responder rates (the non-completer equals failure analysis [NC = F]), patients who terminated the study early for any reason, or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA above 50 or above 400 copies/ml at the missing time points.

Table 3: Efficacy results for study 006

Responder rates (NC = Fa)                       Mean change
Plasma HIV-RNA                                   from baseline­CD4 cell count
< 400 copies/ml                   < 50 copies/ml              cells/mm3 (95 % C.I.b)                     (95 % C.I.b)               (S.E.M.c) Treatment           n            48 weeks                          48 weeks                 48 weeks Regimend
EFV +          202                 67 %                              62 %                      187 ZDV + 3TC                      (60 %, 73 %)                      (55 %, 69 %)                 (11.8) EFV + IDV      206                 54 %                              48 %                      177 (47 %, 61 %)                      (41 %, 55 %)                 (11.3) 

Responder rates (NC = Fa)                                Mean change Plasma HIV-RNA                                             from baseline­CD4 cell count
< 400 copies/ml                          < 50 copies/ml                 cells/mm3 (95 % C.I.b)                             (95 % C.I.b)                 (S.E.M.c) IDV +              206                  45 %                                     40 %                          153 ZDV + 3TC                           (38 %, 52 %)                             (34 %, 47 %)                    (12.3) a   NC = F, noncompleter = failure.
b   C.I., confidence interval.
c   S.E.M., standard error of the mean.
d   EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir.

Long-term results at 168 weeks of study 006 (160 patients completed study on treatment with EFV +IDV, 196 patients with EFV + ZDV + 3TC and 127 patients with IDV + ZDV + 3TC, respectively), suggest durability of response in terms of proportions of patients with HIV RNA < 400 copies/ml, HIV RNA < 50 copies/ml and in terms of mean change from baseline CD4 cell count.

Efficacy results for studies ACTG 364 and 020 are found in Table 4. Study ACTG 364 enrolled 196 patients who had been treated with NRTIs but not with PIs or NNRTIs. Study 020 enrolled 327 patients who had been treated with NRTIs but not with PIs or NNRTIs. Physicians were allowed to change their patient’s NRTI regimen upon entry into the study. Responder rates were highest in patients who switched NRTIs.

Table 4: Efficacy results for studies ACTG 364 and 020

Responder rates (NC = Fa)                     Mean change from
Plasma HIV-RNA                          baseline­CD4 cell count
Study Number/                     n      %       (95 % C.I.c)    %    (95 % C.I.)            cells/mm3 (S.E.M.d) Treatment Regimensb
Study ACTG 364                            < 500 copies/ml               < 50 copies/ml 48 weeks
EFV + NFV + NRTIs                65      70        (59, 82)         ­­­          ­­­              107           (17.9) EFV + NRTIs                      65      58        (46, 70)         ­­­          ­­­              114           (21.0) NFV + NRTIs                      66      30        (19, 42)         ­­­          ­­­               94           (13.6) 
Study 020                                 < 400 copies/ml               < 50 copies/ml 24 weeks
EFV + IDV + NRTIs               157      60        (52, 68)         49        (41, 58)            104            (9.1) IDV + NRTIs                     170      51        (43, 59)         38        (30, 45)             77            (9.9) a  NC = F, noncompleter = failure.
b  EFV, efavirenz; ZDV, zidovudine; 3TC, lamivudine; IDV, indinavir; NRTI, nucleoside reverse transcriptase inhibitor; NFV, nelfinavir.
c C.I., confidence interval for proportion of patients in response.
d S.E.M., standard error of the mean.

---, not performed.

Paediatric population: ACTG 382 is an ongoing uncontrolled study of 57 NRTI-experienced paediatric patients (3 - 16 years) which characterises the pharmacokinetics, antiviral activity and safety of efavirenz in combination with nelfinavir (20 - 30 mg/kg given three times a day) and one or more NRTIs. The starting dose of efavirenz was the equivalent of a 600 mg dose (adjusted from calculated body size based on weight). The response rate, based on the NC = F analysis of the percentage of patients with plasma HIV-RNA < 400 copies/ml at 48 weeks was 60 % (95 %, C.I. 47, 72), and 53 % (C.I. 40, 66) based on percentage of patients with plasma HIV-RNA < 50 copies/ml. The mean CD4 cell counts were increased by 63 ± 34.5 cells/mm3 from baseline. The durability of the response was similar to that seen in adult patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

Peak efavirenz plasma concentrations of 1.6 - 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. Time to peak plasma concentrations (3 - 5 hours) did not change following multiple dosing and steady-state plasma concentrations were reached in 6 - 7 days.

In HIV infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were linear with 200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily, steady state Cmax was 12.9 ± 3.7 µM (29 %) [mean ± S.D. (% C.V.)], steady state Cmin was 5.6 ± 3.2 µM (57 %), and AUC was 184 ± 73 µM·h (40 %).

Effect of food

The AUC and Cmax of a single 600 mg dose of efavirenz film-coated tablets in uninfected volunteers was increased by 28 % (90 % CI: 22 – 33 %) and 79 % (90 % CI:58 – 102 %), respectively, when given with a high fat meal relative to when given under fasted conditions (see section 4.4).

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 efavirenz 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.

Biotransformation

Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolised 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 and that it inhibited P450 isozymes 2C9, 2C19, and 3A4. In in vitro studies efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically.

Efavirenz plasma exposure may be increased in patients with the homozygous G516T genetic variant of the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however, the potential for an increased frequency and severity of efavirenz-associated adverse events cannot be excluded.

Efavirenz has been shown to induce CYP3A4 and CYP2B6, resulting in the induction of its own metabolism which may be clinically relevant in some patients. In uninfected volunteers, 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 compared with single dose administration (see below). Efavirenz has also been shown to induce UGT1A1. Exposures of raltegravir (a UGT1A1 substrate) are reduced in the presence of efavirenz (see section 4.5, table 2).
Although in vitro data suggest that efavirenz inhibits CYP2C9 and CYP2C19, there have been contradictory reports of both increased and decreased exposures to substrates of these enzymes when coadministered with efavirenz in vivo. The net effect of coadministration is not clear.

Elimination

Efavirenz has a relatively long terminal half-life of at least 52 hours after single doses and 40 - 55 hours after multiple doses. Approximately 14 - 34 % of a radiolabelled dose of efavirenz was recovered in the urine and less than 1 % of the dose was excreted in urine as unchanged efavirenz.

Hepatic impairment

In a single-dose study, half life was doubled in the single patient with severe hepatic impairment (Child-Pugh Class C), indicating a potential for a much greater degree of accumulation. 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.

Gender, race, elderly

Although limited data suggest that females as well as Asian and Pacific Island patients may have higher exposure to efavirenz, they do not appear to be less tolerant of efavirenz. Pharmacokinetic studies have not been performed in the elderly.

Paediatric population

In 49 paediatric patients receiving the equivalent of a 600 mg dose of efavirenz (dose adjusted from calculated body size based on weight), steady state Cmax was 14.1 µM, steady state Cmin was 5.6 µM, and AUC was 216 µM·h. The pharmacokinetics of efavirenz in paediatric patients were similar to adults.