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Once-daily nevirapine dosing: a pharmacokinetics, efficacy and safety review
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HIV Medicine
Volume 8 Issue 1 Page null - January 2007
CL Cooper11University of Ottawa, The Ottawa Hospital Division of Infectious Diseases, The Ottawa Health Research Institute, Ottawa, Ontario, Canada and
RPG van Heeswijk11University of Ottawa, The Ottawa Hospital Division of Infectious Diseases, The Ottawa Health Research Institute, Ottawa, Ontario, Canada
1University of Ottawa, The Ottawa Hospital Division of Infectious Diseases, The Ottawa Health Research Institute, Ottawa, Ontario, Canada
Abstract
In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC50) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of once-daily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation.
Introduction
Studies have shown that near complete adherence (>95%) to a prescribed antiretroviral regimen is required to achieve long-term suppression of viral replication [1,2]. It is well known that suboptimal adherence results in the development of drug-resistant viral strains and subsequent virological treatment failure. Adherence is inversely related to the number of doses per day [3,4]. In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-infected patients. A growing number of drugs of several classes are licensed for once-daily dosing (e.g. tenofovir, efavirenz and atazanavir). In addition, the feasibility of once-daily dosing of drugs that are licensed for twice-daily dosing is being explored.
Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC50) of wild-type virus in patients. For this reason, it may be considered for once-daily dosing. The pharmacokinetics, efficacy and safety of nevirapine (Viramune; Boehringer Ingelheim, Ridgefield, CT) in a once-daily [400 mg once a day (qd)] vs twice-daily [200 mg twice a day (bid)] dosing regimen are considered in this review.
Methods
A Medline search using the headings 'nevirapine', 'pharmacokinetics' and 'dosing' was performed to identify published, peer-reviewed literature of relevance to this report. Abstracts from major international HIV/AIDS meetings were reviewed. Where possible, conclusions and recommendations are based on peer-reviewed, published material. In the absence of available data, recommendations are opinion-based.
Clinical pharmacology of nevirapine
Pharmacokinetics
Nevirapine is a small, lipophilic molecule (molecular weight 266.30) that is rapidly and almost completely absorbed after oral administration in humans. Maximum nevirapine plasma concentrations are achieved at about 4 h after drug administration, and the absolute bioavailability is 93% for the tablet formulation (Table 1). Approximately 60% of nevirapine is bound to plasma proteins (predominantly albumin). Nevirapine is extensively distributed in the body, with cerebral spinal fluid (CSF) and semen having concentrations of about 30 and 60%, respectively, of corresponding plasma concentrations. Ingestion of nevirapine together with food delays the absorption, but does not affect the bioavailability. Nevirapine can thus be taken with or without food [5].
Nevirapine is extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes 3A4 and 2B6, and is mainly excreted into the urine as glucuronidated and hydroxylated metabolites (80%) and as parent drug (5%) [5]. Nevirapine causes induction of its metabolism, resulting in a 1.5- to 2-fold increase in the oral clearance during the first weeks of dosing. The plasma elimination half-life is about 45 h after a single dose, and about 25-30 h during steady-state dosing [5]. The licensed dosage for nevirapine is 200 mg twice-daily, after a starting dose of 200 mg once-daily during the first 2 weeks of therapy. Summary statistics of the steady-state plasma pharmacokinetic parameters of nevirapine 200 mg twice-daily in HIV-1-infected patients are presented in Table 1 [6].
Population pharmacokinetic analyses have identified several covariates that may contribute to the observed interindividual variation in the pharmacokinetics of nevirapine (Table 2). However, these covariates are not consistent across studies and have only a moderate effect on nevirapine clearance (up to 30%). Weight, hepatitis C virus (HCV) infection status and baseline aspartate aminotransferase (AST) levels were identified as significant covariates in one out-patient cohort study [7]. Gender, geographical region, and hepatitis B virus (HBV) status were identified in the 2NN study [8]. Both analyses utilized a nonlinear mixed-effects, one-compartment model with first-order absorption and elimination. The factors identified to be related to nevirapine clearance in at least two independent studies included gender (reduced clearance in women [8,9]) and race (reduced clearance in Asian and Negroid races [10,11]). A trend towards a similar race effect on nevirapine clearance was noted in an additional analysis [7].
Pharmacokinetics of nevirapine once-daily vs twice-daily
The steady-state plasma pharmacokinetics of nevirapine after administration of 400 mg once-daily and 200 mg twice-daily was investigated in a randomized, balanced, two-way cross-over bioequivalence study in 20 HIV-1-infected patients [6]. Pharmacokinetic parameters of nevirapine were calculated using standard noncompartmental methods (Table 1). The median plasma nevirapine concentration-time profiles are shown in Fig. 1.
The exposure to nevirapine, measured as the area under the plasma concentration vs time curve from 0 to 24 h (AUC024 h), was comparable for the once-daily and twice-daily dosing regimens. Furthermore, the elimination half-life, clearance and volume of distribution were not different between the two dosing regimens. However, the maximum and trough nevirapine concentrations were higher and lower, respectively, in the once-daily dosing regimen compare with the twice-daily regimen [6].
The median nevirapine plasma concentration at the end of the dosing interval (Cmin) was about 23% lower during once-daily dosing compared with twice-daily dosing [2.88 μg/mL (2.33-4.09 μg/mL) vs 3.73 μg/mL (3.20-5.08 μg/mL), respectively; P<0.01]. A similar difference in nevirapine trough concentration between once- and twice-daily dosing has been observed in the 2NN study [8].
Nevirapine pharmacokinetic properties and virological response
A number of studies have explored the relationships between the pharmacokinetics of nevirapine and the virological response to therapy (Table 3). These have included both once- and twice-daily nevirapine dosing schedules. As the steady-state nevirapine trough concentrations (median about 4000 ng/mL) are far above the concentration required to inhibit 50% viral replication in vitro (the IC50 of nevirapine for wild-type virus is 10.6 ng/mL), no relationships between nevirapine concentrations observed in clinical practice and virological response were anticipated. However, some studies did find relationships between nevirapine concentrations and virological response [12-14]. These findings have not been consistent across studies and are probably confounded by suboptimal adherence.
The INCAS study demonstrated a positive relationship between nevirapine concentrations and virological response [12]. In 51 antiretroviral-naive patients treated with zidovudine, didanosine and nevirapine 200 mg twice-daily, it was found that high exposure to nevirapine determined by random sampling of plasma concentration was positively and significantly associated with the elimination rate constant of plasma HIV-1 RNA during the first 2 weeks of therapy (initial response), as well as with the time to reach an undetectable plasma viral load, and with the success of therapy after 52 weeks (long-term response). Based on this study, a threshold nevirapine plasma concentration of 3.5 μg/mL has been proposed [12,15]. Samples for analysis of nevirapine concentrations were collected at random times post ingestion (time of drug intake unknown). Because of the long elimination half-life of nevirapine, single concentration measurements may be representative of the total exposure during the dosing interval, especially during twice-daily dosing [16]. Of greater concern is the lack of adherence measures in this study. The reported pharmacokinetic (PK)-pharmacodynamic (PD) relationships may be a reflection of the well-known negative effects of suboptimal adherence on drug concentrations and virological response.
Nevirapine pharmacokinetic relationships with toxicity
Several studies have evaluated the relationship between elevations in liver enzymes and nevirapine concentrations. These have included both once- and twice-daily nevirapine dosing schedules. The majority of studies did not find a significant association between changes in AST or alanine aminotransferase (ALT) and nevirapine exposure (Table 4). Although some studies reported higher nevirapine concentrations in patients with elevated liver enzymes, it remains unclear whether high nevirapine concentrations caused toxicity or whether nevirapine clearance was reduced as a result of existing hepatic abnormalities, as suggested in a population pharmacokinetic study where nevirapine clearance was reduced by 13.2% in patients with a baseline AST>1.5 times the upper limit of normal [7].
The beneficial effect of a low-dose lead-in period with regard to the development of rash suggests a relationship with nevirapine trough and AUC concentrations (Table 4). This has been confirmed in some but not all studies. One study reported a 2.3-fold increased risk of rash in patients with random nevirapine concentrations above 5.3 μg/mL [17]. In another study in patients using nevirapine 200 mg twice-daily, it was found that patients with rash had significantly higher trough concentrations after 2 weeks of dosing compared with those without rash (median trough concentrations were, respectively, 5.0 and 3.6 ng/mL; P=0.012) [18]. Of note, AUC and the maximum plasma concentration (Cmax) were not measured in this study so it is not possible to determine whether these may have been better predictors of rash risk. Although these studies suggest an upper limit for the therapeutic window of nevirapine, there is no consensus and a maximum safe nevirapine concentration has not yet been established. Furthermore, in a study by Launay et al., nevirapine trough concentrations at week 2 were comparable between patients with (n=16) and without (n=130) rash (mean nevirapine concentrations were 3.36 and 3.48 μg/mL, respectively; P=0.2) [19].
In an analysis of PK-PD relationships between nevirapine pharmacokinetics and adverse events in the 2NN study, no significant relationships were observed after adjusting for known risk factors such as female gender, CD4 count and hepatitis coinfection [20].
In summary, conflicting results have been reported on the possible relationships between nevirapine pharmacokinetics and the development of adverse events (e.g. rash or hepatic toxicity). Of note, the largest study to evaluate PK-PD relationships for nevirapine to date (i.e. the 2NN study) did not find significant relationships between nevirapine pharmacokinetic parameters and adverse events.
Clinical studies of once-daily nevirapine
Several clinical trials which evaluated the safety and efficacy of nevirapine in a once-daily dosing regimen are summarized below. Of these, the 2NN study is the largest and best known of the trials evaluating this dosing strategy [21].
In the 2NN study, antiretroviral-naive patients were randomized to one of four treatment arms; (1) nevirapine 400 mg once-daily, (2) nevirapine 200 mg twice-daily, (3) efavirenz 600 mg once-daily, or (4) nevirapine 400 mg once-daily plus efavirenz 800 mg once-daily, all in combination with stavudine (40 mg twice-daily) and lamivudine (150 mg twice-daily). In each treatment group, nevirapine was started at a dose of 200 mg once-daily for 2 weeks prior to dose escalation to 400 mg/day. This section focuses on once-daily (n=220) and twice-daily (n=387) nevirapine recipients.
In the primary efficacy analysis (i.e. composite endpoint of virological failure, disease progression and therapy change), the proportion of treatment failures on or before week 48 was 43.6% in once-daily recipients and 43.7% in the twice-daily dosing group. A greater proportion of twice-daily dosed patients (18.9%) were virological failures compared with once-daily recipients (11.4%; P=0.016). The proportion of patients with a plasma HIV-1 RNA concentration<50 copies/mL at 48 weeks was comparable between the groups in the intent-to-treat analysis (70.0% in the once-daily group and 65.4% in the twice-daily group; P=0.24) [21].
There was a trend towards greater change of treatment regimen in the once-daily group (29.1%) vs the twice-daily group (22.0%; P=0.05) which can be accounted for by differences in adverse events. The incidence of all grade 3 or 4 clinical adverse events was comparable in the two treatment arms (15.0 and 20.4% for once-daily and twice-daily dosing, respectively; P=0.098). Grade 3 or 4 clinical hepatitis and rash occurred in 1.4 and 4.1% of the patients, respectively, in the once-daily group compared with 2.1 and 3.4%, respectively, in the twice-daily group. However, significantly more patients experienced hepatobiliary laboratory abnormalities in the once-daily group (13.6%) compared with twice-daily nevirapine recipients (8.3%; P=0.036). More patients in the once-daily group temporarily or permanently discontinued therapy because of rash (12.3%) or hepatic laboratory abnormalities (5.9%) compared with the twice-daily group (6.5 and 2.3%, respectively). Of note, the frequency of asymptomatic and symptomatic hepatic events was higher in Thai patients (16.3 and 10.2%, respectively) than in the rest of the study population (6.2 and 5.6%, respectively) (manuscript in preparation). In a subanalysis excluding patients from Thailand and controlling for CD4 count, the frequency of hepatic events was similar between once- and twice-daily dosed nevirapine. It is unclear why the frequency of hepatic events at a single Thai site was so much higher in patients receiving once-daily dosing. The role of race in predicting liver toxicity deserves further evaluation. Recall that nevirapine pharmacokinetics had no significant relationship with adverse events in this study when data were adjusted for known female gender, CD4 count and hepatitis coinfection [20].
The Spanish Scan Study randomized 94 antiretroviral-naive patients to either nevirapine 400 mg once-daily plus didanosine 400 mg once-daily (n=47) or nevirapine 200 mg twice-daily plus didanosine 200 mg twice-daily (n=47), both in combination with stavudine 40 mg twice-daily [22]. Patients in both treatment arms started nevirapine at a dosage of 200 mg once-daily for the first 2 weeks. The virological and immunological response was comparable between the treatment arms after 80 weeks of follow up. After 12 months of treatment, the respective percentages of patients with plasma viral loads below 200 HIV-1 RNA copies/mL were 73 and 68% for the once-daily and twice-daily regimens (intent-to-treat analysis). No differences were observed in the occurrence of adverse events between the dosing regimens. Four patients (8.5%) discontinued the once-daily regimen (two because of skin rash/fever, one because of pancreatitis, and one because of lipodystrophy) vs three (6.4%) in the twice-daily regimen (all because of skin rash/fever). Hepatitis was reported for four subjects in the twice-daily group and for none in the once-daily group [22].
The VIRGO study was a nonrandomized study of didanosine 400 mg once-daily plus stavudine 40 mg twice-daily, plus nevirapine at a dose of 200 mg twice-daily or 400 mg once-daily in antiretroviral-naive patients [23]. The first 60 patients started nevirapine with the twice-daily dose, and the subsequent 40 patients received the once-daily dose. Patients in both cohorts had comparable baseline characteristics [i.e. 77% male, mean age 37 years, mean weight 66 kg, mean CD4 count 432 cells/μL), although there were slightly more patients with high viral loads (>100 000 copies/mL) in the nevirapine once-daily group. This could potentially bias the virological results in favour of the twice-daily cohort. After 24 weeks of therapy, the percentages of patients with a plasma viral load<50 copies/mL were 55 and 67%, respectively, in the once-daily and twice-daily groups (intent-to-treat analysis). This difference was not significant. Overall, the rate of adverse events was similar for the two dosing regimens. Six patients in each group discontinued therapy because of intolerance (rash in eight patients and transaminitis in four). Treatment-related rash occurred in 24% of patients in the twice-daily cohort, and 23% in the once-daily cohort. The incidence of rash was significantly increased in patients who did not adhere to the recommended dose escalation during the initial weeks of therapy; seven of nine (78%) of such patients developed rash compared to 17 of 90 (19%) of those who adhered to the lead-in period.
Negredo et al. studied the safety and efficacy of switching patients from various twice-daily regimens (with or without nevirapine) to once-daily nevirapine 400 mg, didanosine 400 mg and tenofovir 300 mg [24]. A total of 196 patients were recruited, 85 of whom were switched to the once-daily regimen [note that 21 patients (25%) were on nevirapine prior to the switch, but results for this subgroup were not reported]. After 48 weeks, 65 of 85 patients (76%) in the once-daily group maintained a plasma viral load below 50 copies/mL, vs 72 of 84 (86%) in the group that continued their existing twice-daily regimen (P=0.176). Adverse events leading to treatment discontinuation were more common in the once-daily group. Three subjects (3.6%) who continued twice-daily dosing stopped therapy vs 12 subjects (14.1%) who switched to once-daily dosing (five cases of nevirapine-related hepatitis, two of acute pancreatitis, two of skin rash, one of peripheral neuropathy and two of xerostomia). After 48 weeks, 97% of patients in the once-daily group reported appropriate adherence vs 69.2% of the patients who continued their twice-daily regimen. These data suggest that the benefit of improved adherence may be more than offset by increased adverse events and, in this switch study, possibly reduced virological efficacy.
In summary, several clinical studies in antiretroviral-naive HIV-1-infected patients suggest a similar virological and immunological response to nevirapine in a dose of 400 mg once-daily vs 200 mg twice-daily. The frequency of hepatic abnormalities with once-daily nevirapine is dependent on gender, CD4 count and perhaps race. Severe rash was more common with once-daily dosing in the 2NN study. Although not observed in other nonrandomized studies of once-daily nevirapine, this and liver concerns remain significant obstacles to routine use of this dosing strategy.
Discussion
Many patients prefer once-daily dosed regimens of low pill count and without dietary restrictions [3,4]. This dosing strategy may improve adherence and treatment outcomes. The pharmacokinetic characteristics, efficacy and safety profile of nevirapine were reviewed to determine whether nevirapine 400 mg once-daily based antiretroviral therapy can currently be recommended for these patients.
Once-daily nevirapine dosing results in lower Cmin levels compared with twice-daily treatment [6,8]. However, these pharmacokinetic studies support once-daily dosing assuming that optimal adherence is maintained. Furthermore, the body of work evaluating the clinical efficacy of once-daily nevirapine in treatment-naive patients suggests that the proportion of those achieving and maintaining virological suppression at 1 year of treatment is comparable to that for twice-daily dosing regimens [21,22].
Unfortunately, when compared with twice-daily dosing, antiretroviral regimens in which nevirapine is dosed at 400 mg once-daily immediately after a 2-week lead-in period are associated with an increased risk of rash leading to treatment interruption or discontinuation [21]. The risk of liver complications is another lingering concern [21,24]. For these reasons, once-daily nevirapine cannot be recommended at this time. The pathophysiology of this increased adverse event rate is not fully understood. Although the increased Cmax with once-daily nevirapine has been proposed, little evidence to corroborate this can be found within published pharmacokinetic analyses [20]. Risk factors other than high nevirapine exposure including sex, baseline CD4 count, hepatitis coinfection, race, and genetic profile appear to be important predictors of adverse events associated with nevirapine therapy. It is well accepted that the selection of nevirapine as part of an antiretroviral regimen and its dosing schedule should be based on individual patient characteristics.
Once-daily nevirapine dosing may still have a future. Results from animal and clinical studies suggest that tolerance to high nevirapine concentrations may develop when a dose-escalation approach is used during the first weeks of therapy [25-27]. It is theoretically possible that the benefits of once-daily dosing can be achieved without excess toxicity by switching to once-daily nevirapine only after several months of twice-daily administration. Furthermore, this strategy may allow for identification of patients with hypersensitivity to nevirapine prior to exposing them to higher maximum nevirapine concentrations. This dosing strategy is currently under evaluation in Spain in the NODy study. This randomized, open-labelled, multicentred study of 400 patients already on twice-daily nevirapine for at least 3 months will evaluate the safety as well as the virological and immunological efficacy of switching to once-daily nevirapine compared with remaining on twice-daily treatment.
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