Pharmacokinetics Of Nevirapine Research Articles

Population Pharmacokinetics of Nevirapine in Thai HIV-Infected Patients

Nevirapine-based antiretroviral therapy is widely used as a first-line treatment for HIV-infected patients in resource-limited settings. Nevirapine plasma concentration has been shown to be associated with virological response and treatment failure. Therefore, identifying sources of the variability of nevirapine pharmacokinetics is important for dose optimization. The purpose of the current study was to determine the population mean pharmacokinetic parameters and identify factors that influence pharmacokinetic parameters of nevirapine in Thai HIV-infected patients. The model was developed by a non-linear mixed-effects modelling approach using NONMEM. Model validation was performed using bootstrap analysis and external validation. Additionally, nevirapine plasma concentrations of 200 mg twice daily (NVPBID) and 400 mg once daily (NVPOD) were simulated using the final model to investigate the impact of the covariates and different dosage regimens on nevirapine steady state concentrations. The apparent clearance (CL/F) of nevirapine estimated from this population was 2.51 l/h which is lower than the values previously reported in other populations. The concomitant use of rifampicin increased CL/F by 20%. Simulated nevirapine plasma concentrations from NVPBID were superior to the NVPOD regimen. This population-based pharmacokinetic model can be used for optimizing nevirapine dosage regimens for individual patients to improve efficacy and safety of nevirapine therapy in this population.

Is nevirapine dose-escalation appropriate in young, African, HIV-infected children?

Young children metabolize nevirapine faster than older children/adults. We evaluated nevirapine pharmacokinetics with or without dose-escalation in Zambian, HIV-infected infants/children and its relationship with safety/efficacy. A retrospective pharmacokinetic substudy of the CHAPAS-1 trial. HIV-infected, Zambian children were randomized to initiate antiretroviral therapy (ART) with full-dose twice-daily nevirapine versus 2-week nevirapine dose-escalation. Samples taken 3-4 h postmorning-dose 2 weeks after nevirapine initiation were assayed for nevirapine levels. Viral load was measured on available samples at weeks 4 and 48; adverse events were prospectively reported. Of 162 (77%) children with week-2 samples, 79 (49%) were randomized to nevirapine dose-escalation. At ART initiation, median [interquartile range (IQR)] age, weight and CD4% were 5.2 (1.5-8.7) years, 13.0 (8.1-19.0) kg and 13 (8-18)%, respectively; 81 (50%) were male. With full dose, few children aged less than 2 years (3/23, 13%) or more than 2 years (4/60, 7%) had subtherapeutic nevirapine levels (defined as <3.0 mg/l), but with dose-escalation, seven out of 22 (32%) aged less than 2 years versus seven out of 57 (12%) more than 2 years had subtherapeutic nevirapine levels (P=0.05). There was no difference between week-2 nevirapine levels in those with viral load more than 250 versus less than 250 copies/ml at week 4 (P=0.97) or week 48 (P=0.40). Eleven out of 162 children had grade 1/2 rash; all were more than 2 years of age (P=0.04), and 10 were randomized to full dose. Subtherapeutic nevirapine levels 3-4 h postdose were more frequent in young children on dose-escalation. Younger children were at lower risk for rash. To simplify ART initiation and reduce the risk of suboptimal dosing, full-dose nevirapine at ART initiation should be considered for African HIV-infected children less than 2 years of age.

Evaluation of nevirapine dosing recommendations in HIV‐infected children

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used for chronic human immunodeficiency virus infections in adults and children. The aims of this study were to investigate the population pharmacokinetics of NVP in children, establish factors that influence NVP pharmacokinetics and evaluate the current dosing recommendations. Concentrations were measured on a routine basis in 94 children aged from 2 months to 17 years. A total of 390 NVP plasma concentrations were retrospectively collected, and a population pharmacokinetic model was developed with Monolix 4.0. Nevirapine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. After standardization to a 70 kg adult using allometry, postmenstrual age had a significant effect on the bioavailability. Estimates of apparent clearance and volume of distribution were 3.9 l h(-1) (70 kg)(-1) and 140 l (70 kg)(-1) , respectively. Based on simulations of European Medicines Agency (EMA) and World Health Organization (WHO) dosing recommendations, the probability of observing minimal concentrations below the efficacy target of 3 mg l(-1) is higher following the EMA recommendations than the WHO recommendations. However, NVP underdosing persists for the 3-6 and 6-10 kg weight ranges following the WHO recommendations. It is suggested to increase doses to 75 and 100 mg twice daily for the 3-6 and 6-10 kg weight ranges, respectively, in order to obtain more than 95% of children with concentrations above 3 mg l(-1) .

The pharmacokinetics of nevirapine when given with isoniazid in South African HIV-infected individuals.

Isoniazid preventive therapy (IPT) is recommended in patients on antiretroviral treatment. Isoniazid (INH) inhibits CYP3A4, which metabolises nevirapine (NVP). Administration of INH may cause higher NVP concentrations and toxicity. We studied the effect of INH on NVP concentrations in 21 patients randomised to either placebo (n = 13) or INH (n = 8) in an ongoing trial of IPT in patients on ART. INH was associated with a 24% increase in median NVP area under the plasma concentration-time curve for the 12 h dosing interval, which was not statistically significant (P = 0.66).

Population Pharmacokinetic Analysis of a Nevirapine‐Based HIV‐1 Prevention of Mother‐to‐Child Transmission Program in Uganda to Assess the Impact of Different Dosing Regimens for Newborns

Single-dose nevirapine for mothers and newborns at delivery is the simplest prevention strategy for vertical HIV-1 transmission and hence widely used in resource-constrained settings. HIV-1-positive mothers and newborns received single-dose nevirapine in a prevention of mother-to-child HIV-1 transmission (PMTCT) program in Uganda. In a pharmacokinetic investigation, breast milk and plasma samples of mothers and newborns were collected. The nonlinear mixed-effects modeling approach was suitable for analysis (average: 1.8 samples/matrix/individual). For describing the nevirapine pharmacokinetics in mothers and newborns, a 1-compartment model was demonstrated to be sufficient. The plasma-placenta transfer could be quantified, revealing a transfer fraction of 11% to 25% (with a significant influence of time span between maternal nevirapine intake and birth) and a high transfer rate constant from maternal drug administration. Interindividual variability was moderate between mothers and high between newborns. Simulations revealed that newborns born early (<1 hour) after maternal nevirapine intake would benefit from a 3-fold higher nevirapine dosage (6 mg/kg) after birth for analogous protective plasma concentrations over the first 2 weeks. In contrast, postnatal nevirapine dosage seemed to be dispensable for newborns born late (>24 hours) after maternal nevirapine intake. These dosing recommendations should be evaluated in prospective studies, including additional antiretroviral drugs in accordance with current PMTCT guidelines.

Integration of data from multiple sources for simultaneous modelling analysis: experience from nevirapine population pharmacokinetics

To propose a modelling strategy to efficiently integrate data from different sources in one simultaneous analysis, using nevirapine population pharmacokinetic data as an example. Data from three studies including 115 human immunodeficiency virus-infected South African adults were used. Patients were on antiretroviral therapy regimens including 200 mg nevirapine twice daily and sampled at steady state. A development process was suggested, implemented in NONMEM7 and the final model evaluated with an external data set. A stepwise approach proved efficient. Model development started with the intensively sampled data. Data were added sequentially, using visual predictive checks for inspecting their compatibility with the existing model. Covariate exploration was carried out, and auxiliary regression models were designed for imputation of missing covariates. Nevirapine pharmacokinetics was described by a one-compartment model with absorption through two transit compartments. Body size was accounted for using allometric scaling. The model included a mixture of two subpopulations with different typical values of clearance, namely fast (3.12 l h(-1)) and slow metabolizers (1.45 l h(-1)), with 17% probability of belonging to the latter. Absorption displayed large between-occasion variability, and food slowed the absorption mean transit time from 0.6 to 2.5 h. Concomitant antitubercular treatment including rifampicin typically decreased bioavailability by 39%, with significant between-subject variability. Visual predictive checks of external validation data indicated good predictive performance. The development strategy succeeded in integrating data from different sources to produce a model with robust parameter estimates. This work paves the way for the creation of a nevirapine mega-model, including additional data from numerous diverse sources.

Pharmacokinetics of nevirapine in HIV-infected children under 3 years on rifampicin-based antituberculosis treatment

There is an urgent need to optimize cotreatment for children with tuberculosis and HIV infection. We described nevirapine pharmacokinetics in Zambian children aged less than 3 years, cotreated with nevirapine, lamivudine and stavudine in fixed-dose combination (using WHO weight bands) and rifampicin-based antituberculosis treatment. Twenty-two children received antituberculosis and antiretroviral therapy (ART) concurrently for 4 weeks before pharmacokinetic sampling. Plasma nevirapine concentrations were determined in samples taken immediately before, and 1, 2 and 6 h after an observed dose. Nevirapine pharmacokinetics were compared with those in 16 children aged less than 3 years without tuberculosis. Twenty-two children were treated for HIV/TB coinfection, 10 of whom were girls. One boy was excluded from analysis for nonadherence. The median age was 1.6 years (range: 0.7-3.2). Median weight was 8.0 kg (range: 5.1-10.5). The baseline CD4% was 13.1 (range: 3.9-43.6). Median predose concentration of nevirapine was 2.93 mg/l (range: 1.06-11.4), and peak concentration was 6.33 mg/l (range: 2.61-14.5). The nevirapine AUC up to 12 h was estimated as 52.0 mg.h/l (range: 22.6-159.7) compared with 90.9 mg.h/l (range: 40.4-232.1) in children without tuberculosis (P < 0.001). Predose concentrations of nevirapine were less than 3.0 mg/l in 11 children on tuberculosis treatment versus none of the 16 children without tuberculosis treatment (P = 0.001). AUC was 41% (95% CI: 23-54%) lower in children with tuberculosis than without tuberculosis (P < 0.001) after adjusting for dose per square meter. : We found substantial reductions in nevirapine concentrations in young children receiving rifampicin. Further studies are needed to define the pharmacokinetics, safety and efficacy of adjusted doses of nevirapine-based ART in young children with tuberculosis.

Influence of CYP2B6 and ABCB1 SNPs on nevirapine plasma concentrations in Burundese HIV‐positive patients using dried sample spot devices

• Nevirapine pharmacokinetics are affected by several factors including CYP2B6 single nucleotide polymorphisms (SNPs). These genetic profiles are more common in African patients and they affect the drug clearance being associated with higher trough concentrations. Pharmacokinetic/pharmacogenetic (PK/PG) studies are difficult to perform in remote areas where refrigeration is not available, although dried plasma and dried blood methods have been validated. • Dried plasma spots are useful tools for studying nevirapine PK with a good association to plasma concentrations and they can be used in rural areas since a cold chain is not necessary. Dried blood spots can be used to store and analyze patients' DNA for PG polymorphisms. Nevirapine trough concentrations in Burundese patients, not studied so far, are above the target concentration (3000 ng ml(-1) ) in 84% of patients. CYP2B6 (both at position 516 and 983) but not ABCB1 (3435 and 1236) SNPs as well as age correlate with higher nevirapine exposure. The pharmacokinetics (PK) and pharmacogenetics (PG) of nevirapine have been studied in rich and limited-resource countries. CYP2B6 single nucleotide polymorphisms (SNPs) have been associated with decreased drug clearance. We evaluated the PG determinants of nevirapine trough concentrations in a rural cohort in Burundi using easy to store and transport dried sample spot devices. A cross-sectional analysis in HIV-positive nevirapine-treated patients in Kiremba, north of Burundi, was performed in 2009. After blood withdrawal whole blood was stored on dried blood spots and plasma (after centrifugation) was placed on dried plasma spot devices and stored at room temperature. Nevirapine plasma and dried sample spot concentrations were compared to test the clinical usefulness of this method. SNPs in CYP2B6 and ABCB1 (using a real time PCR technique) were analyzed and associated with nevirapine plasma trough concentrations. Nevirapine concentrations measured on dried plasma spot devices were highly related to plasma concentrations in 60 patients, although a negative bias was observed (-18%). Nevirapine trough concentrations were above the target concentration (3000 ng ml(-1) ) in 84% of patients and they were associated with CYP2B6 SNPs (both at position 516 and 983). No effect of ABCB1 SNPs was noted. Dried plasma spot devices are accurate tools for measuring nevirapine concentrations in rural settings where refrigeration is not available, despite a moderate underestimation bias. They allowed the evaluation of nevirapine concentrations in a cohort of HIV-infected people in rural Burundi, confirming very good exposure and correlation with PG polymorphisms in the CYP2B6 encoding gene.

Dosage Optimization of Treatments Using Population Pharmacokinetic Modeling and Simulation

Pharmacokinetic variability in drug levels represent for some drugs a major determinant of treatment success, since sub-therapeutic concentrations might lead to toxic reactions, treatment discontinuation or inefficacy. This is true for most antiretroviral drugs, which exhibit high inter-patient variability in their pharmacokinetics that has been partially explained by some genetic and non-genetic factors. The population pharmacokinetic approach represents a very useful tool for the description of the dose-concentration relationship, the quantification of variability in the target population of patients and the identification of influencing factors. It can thus be used to make predictions and dosage adjustment optimization based on Bayesian therapeutic drug monitoring (TDM). This approach has been used to characterize the pharmacokinetics of nevirapine (NVP) in 137 HIV-positive patients followed within the frame of a TDM program. Among tested covariates, body weight, co-administration of a cytochrome (CYP) 3A4 inducer or boosted atazanavir as well as elevated aspartate transaminases showed an effect on NVP elimination. In addition, genetic polymorphism in the CYP2B6 was associated with reduced NVP clearance. Altogether, these factors could explain 26% in NVP variability. Model-based simulations were used to compare the adequacy of different dosage regimens in relation to the therapeutic target associated with treatment efficacy. In conclusion, the population approach is very useful to characterize the pharmacokinetic profile of drugs in a population of interest. The quantification and the identification of the sources of variability is a rational approach to making optimal dosage decision for certain drugs administered chronically.

Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women

To estimate nevirapine (NVP) pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the AIDS Clinical Trials Group A5208/OCTANE study in Africa. In HIV-infected, nonpregnant women with screening CD4 cell count less than 200 cells/μl randomized to NVP (twice daily, after 14-day once-daily lead-in period) and tenofovir/emtricitabine, single NVP blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of NVP, were defined as toxicity. NVP pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-h area under the curve, and predicted plasma concentrations. Median week 4 NVP clearance was 2 l/h. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and nine (3%) had grade 3+ rash. Median clearance was 1.7 l/h for participants exhibiting 3+ rash versus 2 l/h in women without 3+ rash (P = 0.046). The odds of developing 3+ rash was 50% higher for every 20% decrease in clearance (P = 0.046). NVP discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 cell count more than 250 cells/μl (P = 0.003). In this study, HIV-infected African women starting a NVP-based antiretroviral regimen had a lower NVP clearance compared to previous reports. Severe rash, but not hepatotoxicity, was associated with higher NVP exposure. Albeit observed in a small number of women, baseline CD4 cell count at least 250 cells/μl was significantly associated with NVP toxicity.

Pharmacokinetics of Nevirapine in HIV and Tuberculosis–coinfected Children Receiving Antiretroviral Fixed-dose Combination Tablets While Receiving Rifampicin-containing Tuberculosis Treatment and After Rifampicin Discontinuation

We assessed the pharmacokinetics of nevirapine in HIV and tuberculosis-coinfected children while they were receiving nevirapine-containing fixed-dose combination tablets with rifampicin-based tuberculosis treatment and after discontinuation. The median age (range) was 9.7 (4.4-11.7) years. The nevirapine area under the concentration versus time curve from 0 to 12 hours and trough concentration with rifampicin were 85.3 (40.5-170.7) mg.h/mL and 6.4 (3.00-13.27) mg/mL, respectively, providing adequate exposure.

Associations Between ABCB1, CYP2A6, CYP2B6, CYP2D6, and CYP3A5 Alleles in Relation to Efavirenz and Nevirapine Pharmacokinetics in HIV-Infected Individuals

Human immunodeficiency virus (HIV)-infected individuals show large interindividual variation in response to antiretroviral therapy. Efavirenz (EFV) and nevirapine (NVP) are nonnucleoside reverse transcriptase inhibitors, which are prescribed in combination with other antiretroviral therapy in so-called highly active antiretroviral therapy. Recent studies provide evidence for the role of cytochrome P450 (CYP) genes, in particular CYP2B6, in relation to EFV and NVP pharmacokinetics. In this study, the authors investigated whether common ABCB1, CYP2A6, CYP2B6, CYP2D6, and CYP3A5 alleles are associated with plasma concentrations of EFV and NVP in HIV-infected individuals. Plasma drug concentrations were quantified by high-performance liquid chromatography in 143 HIV-infected individuals receiving either EFV or NVP. Genotyping for common alleles was performed by restriction fragment length polymorphism and Taqman assays. Individuals were genotyped for 11 single-nucleotide polymorphisms in 5 genes. CYP2B6 haplotypes were reconstructed by PHASE. Plasma EFV concentrations were positively associated with CYP2B6 c.516G>T, c.785A>G, and c.983A>G single-nucleotide polymorphisms in HIV-infected individuals. Increased plasma concentrations of EFV and NVP were present in individuals with the CYP2B6*6/*6 or *6/*18 haplotype compared with CYP2B6*1/*1 [increase of 62% (95% confidence interval, 44.0-80.1) and 24% (95% confidence interval, 7.0-40.0), respectively, P < 0.01]. No significant association with other genes in relation to EFV or NVP concentrations was found. In this study, a strong association of CYP2B6*6 and CYP2B6*18 alleles in relation to EFV and NVP plasma concentrations was found, which confirmed previous studies.

Exploration of CYP450 and Drug Transporter Genotypes and Correlations with Nevirapine Exposure in Malawians

Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians. CYP450 2B6, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects. Allele frequencies (variant) were: CYP2B6 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*1B (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP2B6 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27-2.40) for area under the concentration time curve (AUC)(0-12 h), 1.58 (1.03-2.42) for C(0), and 0.53 (0.31-0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP2B6 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027). Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP2B6 516 was significantly associated with nevirapine exposure.

Bioavailability of nevirapine in rats after oral and subcutaneous administration, in vivo absorption from gastrointestinal segments and effect of bile on its absorption from duodenum

Nevirapine is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type-1. The usual dosing regimen is 200 mg twice/day. Reducing the dosing frequency would significantly improve treatment adherence and quality of life of patients. To study new forms of administration, it is necessary to do pre-clinical studies and know the absorption characteristics of nevirapine in laboratory animals. However, there are no studies about its bioavailability in rats and hardly any about its pharmacokinetic. The objectives of this study were to describe the pharmacokinetics of nevirapine in rats after intravenous, oral and subcutaneous administration, to assess its absorption by different regions of the gastrointestinal tract and to evaluate the effect of bile on its intestinal absorption. Nevirapine was well absorbed after oral and subcutaneous administration and the bioavailability estimated in rats (91% for both administration routes) was practically equal to that reported in humans (91–93%) after oral administration of therapeutic doses. Nevirapine was absorbed from the duodenum, ileum and colon, while absorption from the stomach was very low. The rate of absorption was in the order: duodenum > ileum > colon > stomach. The presence of bile in the duodenum increased the absorption rate of nevirapine.

Effect of short term and chronic administration of Sutherlandia frutescens on pharmacokinetics of nevirapine in rats

Sutherlandia frutescens (sutherlandia), an African herbal supplement was recommended by the South African Ministry of Health for the treatment of AIDS patients. However, no reports yet exist delineating the effect of sutherlandia on pharmacokinetics of antiretroviral agents. Therefore, this investigation aimed at screening the effects of short term and chronic exposure of sutherlandia on oral bioavailability and pharmacokinetics of nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, in Sprague Dawley rats. NVP (6 mg/kg) was administered orally alone (control) and with co-administration of sutherlandia; short term (12 mg/kg single dose) and long term (12 mg/kg, once a day for 5 days). No significant difference in the pharmacokinetic parameters of NVP was found upon short-term co-administration of Sutherlandia. However, there was a 50% decrease ( p < 0.05) in the AUC and C max values of NVP after 5 days of chronic exposure with Sutherlandia. In addition, quantitative RT-PCR studies demonstrated a 2–3-fold increase in the hepatic and intestinal mRNA expression of CYP3A2, relative to vehicle control. To further confirm, if this could translate into a clinically relevant pharmacokinetic interaction in patients, we tested this hypothesis employing LS-180 cells as an in vitro induction model for human CYP3A4. Ninety-six hours post treatment, similar to positive control rifampicin (25 μM), sutherlandia extract (300 μg/mL) resulted in elevated m-RNA expression levels and functional activity of CYP3A4 (human homologue of rodent CYP3A2) in LS-180 cells. Taken together, these results suggest that a potential drug–herb interaction is possible when NVP is co-administered with S. frutescens, although this hypothesis still remains to be investigated in a clinical setting.

“Forgiving” a Missed Daily Dose

Editor: adherence is an essential component of a successful drug regimen.1 Simplification of a therapeutic regimen with once-daily treatment options is an important strategy to improve or sustain adherence to treatment. An extended release 400 mg tablet formulation of the nonnucleoside reverse transcriptase inhibitor nevirapine has been developed2 to offer the potential benefit of once-daily highly active antiretroviral therapy (HAART) to HIV-1-positive patients. The double-blind 48-week VERxVE trial with a total of over 1000 patients confirmed the noninferior virologic efficacy of the nevirapine 400 mg extended release once-daily regimen as compared to the standard immediate release 200 mg twice-daily regimen of nevirapine. The extended release formulation also demonstrated minimal peak-to-trough fluctuations in plasma nevirapine levels.3 As a result of metabolic enzyme autoinduction following a month of oral therapy, the half-life of nevirapine (200 mg twice daily) stabilizes at approximately 24 h. Simplification to a once-daily regimen was the objective in developing an extended release formulation. This was achieved by delaying the release of the total nevirapine dose at a slower rate over a 24-h period. Systemic absorption is prolonged for an additional day, thereby minimizing the fluctuations in the peak-to-trough concentrations of the active drug. As long as there is drug in the intestinal tract,4 this smoothing of the circulating drug concentrations leads to a longer timeframe at which the drug is at therapeutic concentrations, thereby minimizing the impact of a single missed dose of extended release nevirapine. Minimizing the impact of a single missed dose is important for a nonnucleoside reverse transcriptase inhibitor (NNRTI) such as nevirapine, as adherence rates of less than 95% have been associated with inadequate long-term treatment outcome.5 In the 2NN study,6 one treatment arm consisting of 208 patients on immediate release nevirapine 400 mg once daily had a median Cmax concentration of 7.88 μg/ml and a trough concentration of 3.26 μg/ml, resulting in a peak-to-trough ratio slightly greater than 2, consistent with dosing based on the half-life of the drug. In the VERxVE trial,3 with 418 patients on nevirapine extended release 400 mg once daily, the trough concentration of 3.50 μg/ml was maintained. However, the estimate of Cmax in a subset of patients was only 3.77 μg/ml, resulting in a peak-to-trough ratio approaching 1, consistent with extended first-order release and absorption matching the elimination rate of the drug. To illustrate the relative impact of a single missed daily dose of nevirapine, data from 2NN (two immediate release tablets for a total of 400 mg) and data from VERxVE (a single 400 mg extended release tablet) were modeled at steady state (4 weeks after treatment initiation), along with a simulation of expected nevirapine concentrations if the next dose was missed (Fig. 1). As illustrated in Fig. 1, trough nevirapine concentrations 48 h after the last dose are 2.1 μg/ml (88 × EC50 of 90 nM) for the extended release dosage form, but only 1.3 μg/ml (54 × EC50) for an immediate release 400 mg (2 × 200 mg tablets) dose taken once daily in an off-label manner. The extended release formulation maintains a 60% greater plasma concentration of nevirapine, a “forgiveness” difference that may be clinically significant for some patients on HAART therapy. Medication adherence to the entire HAART regimen must still be emphasized to the patient in order to avoid functional monotherapy and because consistent missed doses (more than once in 2 weeks) will lower overall systemic nevirapine levels irrespective of “forgiveness.” Consecutively missing more than one day of therapy may require reinitiation of a HAART loading regimen to obtain proper therapeutic levels of each drug and to prevent selection of resistance. FIG. 1. Modeled nevirapine concentration time curves for 2NN and VERxVE trials over a 24-h steady-state interval (troughs of 3.4 μg/ml at 0 and 24 h, respectively) and simulated curves for a missed dose at 24 h (troughs of 2.1 ...

Nevirapine pharmacokinetics when initiated at 200 mg or 400 mg daily in HIV-1 and tuberculosis co-infected Ugandan adults on rifampicin

rifampicin lowers nevirapine plasma concentrations by inducing cytochrome P450. However, few data are available on this interaction during the lead-in period of nevirapine treatment. eighteen HIV-1/tuberculosis co-infected adults receiving rifampicin daily as part of anti-tuberculosis therapy were evenly randomized to nevirapine initiation by dose escalation (NVP200) or nevirapine initiation at 200 mg twice daily (NVP400). Subjects underwent 12 h intensive pharmacokinetic sampling on Days 7, 14 and 21 of nevirapine treatment. A minimum effective concentration (MEC) of 3000 ng/mL was used to interpret nevirapine concentrations 12 h after dosing (C(12)). NCT00617643 (www.clinicaltrials.gov). day 7 geometric mean nevirapine C(12) [90% confidence interval (CI)] was 1504 (1127-2115) ng/mL and 3148 (2451-4687) ng/mL in the NVP200 and NVP400 arms, respectively (P < 0.01). Nevirapine C(12) on Days 14 and 21 was similar. On Day 21, nevirapine concentration in 64% of patients was below the MEC. On Day 7, geometric mean area under the curve (AUC(0-12)) was lower in the NVP200 arm, 25 223 (90% CI, 21 978-29 695) ng·h/mL versus 43 195 (35 607-57 035) ng·h/mL in the NVP400 arm (P < 0.01). Similarly, on Day 14, nevirapine AUC(0-12) was lower in the NVP200 arm 23 668 (18 253-32 218) ng·h/mL versus the NVP400 arm 44 918 (36 264-62 769) ng·h/mL (P = 0.03). in co-treated patients, nevirapine concentrations were below the MEC during initiation with dose escalation. Nevirapine initiation at the maintenance dose of 200 mg twice daily is preferred. Sub-therapeutic nevirapine concentrations were common at Day 21 with either regimen. Evaluation of higher nevirapine maintenance doses may be considered.

Suboptimal Nevirapine Steady-State Pharmacokinetics During Intrapartum Compared With Postpartum in HIV-1-Seropositive Ugandan Women

Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa. This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNA was performed within 2 weeks of each visit. Nevirapine C12 above 3000 ng/mL was classified as optimal based on the suggested value for therapeutic drug monitoring. The pharmacokinetics of nevirapine were influenced by pregnancy, demonstrated by a 20% reduction in the maximum concentration, minimum concentration (C12), and area under the curve between T3 and PP visits (P = 0.001, P = 0.011 and P = 0.005, respectively). Ten subjects (66.7%) had C12 values <3000 ng/mL during T3. Of these participants, 7 partcipant's C12 concentrations increased to >3000 ng/mL during the PP visit. HIV-1 RNA were <1000 copies per milliliter at T3 and <400 copies per milliliter at PP in all patients. Nevirapine exposure was reduced in Ugandan women during their third trimester compared with the same women PP, however, HIV RNA remained <1000 copies per milliliter. The long-term impact of intermittent suboptimal nevirapine concentrations during pregnancy is unknown.

Population Pharmacokinetics of Nevirapine in HIV-1-Infected Pregnant Women and Their Neonates

The aim of the present study was to describe the nevirapine (NVP) pharmacokinetics (PK) in pregnant women and their neonates and to evaluate the transplacental drug transfer and administration scheme for the prevention of mother-to-child transmission. Thirty-eight HIV-1-infected pregnant women were administered one tablet of NVP (200 mg) and two tablets of tenofovir-emtricitabine (Truvada) at the initiation of labor. Children were given NVP syrup (2 mg/kg of body weight) as a single dose (sdNVP) on the first day of life. By pair, NVP concentrations were measured in 11 maternal, 1 cord blood, and 2 neonatal plasma samples and analyzed by a population approach. A one-compartment model was used for mothers and neonates; the absorption rate constants for mothers and neonates were 0.95 h(-1) (intersubject variability, 111%) and 0.39 h(-1), respectively; the apparent elimination clearances were 1.42 liter·h(-1) (intersubject variability, 22%) and 0.035 liter·h(-1), respectively; and apparent volumes of distribution were 87.3 liters (intersubject variability, 25%) and 5.65 liters, respectively. An effect compartment was linked to maternal circulation by mother-to-cord and cord-to-mother rate constants of 1.10 h(-1) and 1.43 h(-1), respectively. Placental transfer, expressed as the fetal-to-maternal area under the curve ratio, was 75%. Neonates had a very long half-lives (110 h) compared to adults. In the 38 mothers, the simulated median individual predicted time during which the NVP concentration remained above the half-maximal inhibitory concentration (IC(50)) was 13.2 days (range, 12 to 19.2 days). Thus, the administration of tenofovir-emtricitabine for at least 3 weeks after delivery should be considered to prevent the emergence of resistant viruses. The neonate must receive sdNVP immediately after birth when the infant is born less than 30 min after maternal drug intake to keep NVP concentrations above the IC(50).

Safety, Censoring, and Intent‐to‐Treat Analysis: Dangers to Generalizability

Though Makadzange et al. efforts are commendable, several safety, methodologic, and reporting issues deserve clarification [1]. First is safety. Fluconazole increases the area-under-the-curve (AUC) of nevirapine in a dose-dependent manner. Nevirapine AUC increases by 29% with 200mg fluconazole given three times weekly, by 50% with 200mg fluconazole daily, and by 90–100% with 400mg fluconazole daily [2–4]. Effects of fluconazole 800mg daily on nevirapine pharmacokinetics are unknown. As only immediate ART subjects were exposed to 800mg fluconazole and nevirapine for 10 weeks, lack of safety monitoring data is not reassuring that increased hepatotoxicity was not contributory to excess mortality. The authors reported, “Liver function test results remained normal throughout the study …” Though this may technically be true, only 44 subjects had baseline ALT measured and monitoring was reported as occurring every 6 months. When nearly half the deaths (17/35) occurred before first follow-up, 15 of 35 occurred at home, and 33 of 35 occurred prior to six months, an assumption of no hepatotoxicity is incorrect in the absence of actual data. Second, the censoring is unclear. The reported mortality with immediate ART was 88% of 28 persons. No integer divided by 28 equals 88%. Based on the text, reported mortality in immediate ART arm was 82.1% (23/28) vs. delayed arm 46.1% (12/26). Of more concern is that outcomes displayed in Figure 2 do not match mortality (n=12) and lost (n=3) for the delayed arm, nor mortality (n=23) and lost (n=3) for the immediate arm as reported in the text and Figure 1. In counting the ‘number at risk’ in Figure 2, for delayed and immediate ART arms, 15 and 24 respective subjects are dead or lost-to-follow up by 200 days, with one additional death in each arm after 200 days. Thus, non-survival rates are: 61.5% (16/26) for delayed vs. 89.3% (25/28) for immediate ART (P=.026). Based on reported mortality (i.e. 12 and 23 deaths), the Kaplan-Meier figure thereby implies 4 subjects were censored in the delayed arm and 2 in the immediate arm. This censoring would yield 54.5% (12/22) and 88% (23/26) mortality (similar to that reported by the authors). The implication is that either participant numbers or outcomes in Figure 1, Figure 2, and/or the text are incorrect as well as that intent-to-treat analysis was not consistently utilized, though stated as such. One fundamental question for any clinical trial is appropriate outcome measures. We would advocate that survival is a better outcome measure than known mortality. Cryptococcal meningitis has a near 100% mortality within 6 months in the absence of ART [5, 6]. In a time-to-event analysis, right-hand censoring is generally considered acceptable for lost-to-follow up, yet we question the appropriateness of doing so in all scenarios. This is particularly germane to 3 (or possibly 4) subjects in the delayed arm who were lost-to-follow-up before 2 weeks and did not initiate ART. Considering them a success by time-to-event analysis before censoring at ≤2 weeks creates a subtle systematic bias. The overall concern is a type-I error due to relatively small sample size, underpowered nature of the trial, inadequacy of randomization (e.g. CD4’s unequal), post-hoc clinicaltrials.gov registration, and further complicated by early stoppage. Unexplained shifts in 1–2 subjects become potentially important. Nevertheless, the overall conclusion is likely correct that after CM when using nevirapine with fluconazole 800mg, immediate ART results in higher mortality. The authors’ conclusion that “early initiation of ART most likely resulted in increased rates of cryptococcal IRIS” is unsubstantiated speculation, as no attempt was made to assess for cryptococcal-IRIS. The final question is whether this trial’s result is generalizable, particularly if efavirenz were used instead of nevirapine, nevirapine dose adjusted to 200mg daily while receiving fluconazole 800mg, amphotericin used, or degree of immunosuppression fully equal. Further trials are needed.