Pharmacokinetic analysis of nevirapine extended release 400 mg once daily vs nevirapine immediate release 200 mg twice daily formulation in treatment-naïve patients with HIV-1 infection

Abstract

Background: VERxVE data showed non-inferior virologic efficacy with extended release nevirapine (NVP-XR) dosed 400 mg once daily (QD) versus immediate release nevirapine (NVP-IR) 200 mg twice daily in a double-blind, non-inferiority study in treatment-naïve HIV-1-positive patients.

Objective: To study the pharmacokinetics (PK) of the NVP formulations and identify possible associations with demographic factors.

Methods: Patients with viral load ≥1000 copies/mL and CD4+ count > 50– <400 cells/mm³ (males) and >50– <250 cells/mm³ (females) at screening received NVP-IR 200 mg QD during a 14-day lead-in and were then stratified by baseline viral load and randomized to NVP-XR or -IR. NVP trough concentrations at steady state (SS) (C_pre,ss,N) were measured up to week 48 for all participating patients. In a PK sub-study, SS parameters – AUC_0–24, C_max, C_min, and peak-to-trough fluctuation were obtained and analyzed with relative bioavailability assessed at week 4 by plasma collection over 24 h.

Results: Trough concentrations were stable from week 4 to week 48 for all patients (n = 1011) with both formulations, with NVP-XR/IR ratios of 0.77–0.82. Overall, 49 patients completed the PK sub-study: 24 XR and 25 IR. NVP-XR showed less peak-to-trough fluctuation (34.5%) than IR (55.2%), and lower AUC_0–24, C_min, C_max, and trough concentrations than IR. However, no effect of SS trough concentrations was found on the virologic response proportion at least up to 1000 ng/mL. No significant association was found between NVP PK and gender, race, and viral load.

Conclusion: These data suggest NVP-XR achieves lower but effective NVP exposure compared with NVP-IR.

Keywords:

• Nevirapine
• Extended release
• Immediate release
• HIV
• Pharmacokinetic
• Virologic efficacy
• Bioavailability

Introduction

Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy has been a popular first regimen of choice for treating human immunodeficiency virus (HIV) infection. Historically, the two most used NNRTIs are nevirapine immediate release (NVP-IR) and efavirenz.^1–3 NVP has a well-characterized efficacy, safety, and tolerability profile^4–6 and is currently prescribed as 200 mg once daily (QD) for the first 14 days and 200 mg twice daily (BID) subsequently.

Considering the substantial pill burden on patients, fixed-dose combinations are recommended as standard of care in HIV, particularly in treatment-naïve patients. Further, clinical studies have shown that treatment adherence is improved with QD versus BID dosing regimens.^7–9 A recent meta-analysis of 11 randomized controlled clinical trials reported that QD dosing regimens significantly improve adherence to antiretroviral therapy compared with more complex regimens.¹⁰ Importantly, a previous pharmacokinetics (PK) study demonstrated that at steady state, exposure to NVP (area under the concentration–time curve from zero to 24 h [AUC_0-24] was not significantly different with NVP-IR 400 mg QD versus 200 mg BID dosing regimen, but peak plasma NVP concentrations were higher (maximum concentration [C_max]: 6.7 vs. 5.4 μg/mL) and trough concentrations were lower (minimum concentration [C_min]: 2.9 vs. 3.7 μg/mL)¹¹ for the QD regimen. A QD extended release NVP formulation (NVP-XR) would allow dosing symmetry with QD nucleoside reverse transcriptase inhibitors (NRTIs), potentially increasing adherence and the resultant efficacy.

NVP has demonstrated absorption throughout the intestinal tract using the Enterion™ site-specific delivery capsule,¹² making it suitable for development as an XR formulation. A study evaluating slow release NVP 300 and 400 mg prototype tablet formulations demonstrated robust predictions of in vivo profiles based on in vitro dissolution profiles.¹³ Subsequently, a study in HIV-1 patients investigating the PK characteristics and safety profile of 400 or 300 mg NVP-XR formulation tablets dosed QD found that both doses resulted in delayed absorption and lower peak plasma concentrations of NVP at steady state compared with NVP-IR BID, but importantly, similar trough plasma concentrations.¹⁴ Based on these results, the NVP-XR 400 mg formulation was selected for further clinical investigations in the phase III VERxVE and TRANxITION trials.^14–16 The VERxVE trial compared the efficacy of treatment with 400 mg NVP-XR dosed QD versus 200-mg BID of the conventional IR formulation in 1011 patients.¹⁵ Both NVP formulations were dosed in combination with NRTIs, emtricitabine and tenofovir, in an antiretroviral therapy-naïve study population with specific CD4+ cell count ranges for males and females as recommended for NVP treatment.^3,17 NVP-XR dosed QD was also shown to be non-inferior to NVP-IR dosed BID, with a similar safety and adverse event profile.¹⁵ On the basis of these results, the NVP-XR formulation was approved in the United States, Canada, the European Union, and several other countries.

Despite previous research on the association of patient demographics with the PK of NNRTIs,^18–22 there is no clear consensus on whether demographic factors like race or gender are significant determinants of NVP concentrations.¹⁹ As part of the VERxVE trial, NVP pre-dose trough concentrations trough concentrations (C_trough) for all participating patients were collected in an optional PK sub-study assessing steady-state PK parameters. This article focuses on the PK data from the trial and determines PK profiles and C_trough in relation to patient demographics and baseline characteristics, in order to identify possible associations.

Methods

Study design and patient population

VERxVE¹⁵ was a randomized, double-blind, double-dummy, active controlled trial which evaluated the PK of NVP-XR 400 mg QD in comparison to NVP-IR 200 mg BID, both in combination with tenofovir/emtricitabine. The trial was conducted in accordance with the International guidelines and regulations and all participants provided written informed consent.¹⁵

Eligible patients¹⁵ were treated with NVP-IR 200 mg QD during a 14-day lead-in period, and were then stratified by viral load (VL) at baseline (≤100,000 vs. >100,000 copies/mL). Patients were randomized 1:1 within each stratum to receive NVP-XR 400 mg QD (plus placebo) or NVP-IR 200 mg BID (plus placebo), both combined with tenofovir 300 mg plus emtricitabine 200 mg QD for a treatment period of at least 48 weeks, with a planned study duration of 144 weeks.

Plasma sample collection

Morning trough (pre-dose) plasma samples were collected at each visit within 1 h before the next planned dose. For the optional PK sub-study only, intensive PK blood samples were collected at 0.5, 1, 2, 3, 4, 6, 8, 11.9, 12.5, 13, 14, 15, 17, and 24 h following the morning drug administration on Day 28. Patients were hospitalized overnight the day before Visit 4 (Day 27) and remained at the center until the last sample was collected.

Plasma NVP measurement

NVP concentrations in plasma samples were analyzed with a high-performance liquid chromatography tandem mass spectrometry assay validated over a concentration range of 25–10,000 ng/mL.²³

VL assay methodology

VL was measured by Covance Laboratory Services using the Roche Cobas® Amplicor Ultrasensitive HIV-1 test. This assay has a very wide range of quantification (48–10,000,000 copies/mL).

PK analysis

A non-compartmental analysis of steady-state PK parameters (C_max, time to reach C_max [t_max], C_min, and AUC_0-24) was carried out using WinNonlin v5.3 (Pharsight, CA, USA). Descriptive statistics were calculated for trough plasma concentrations for all patients, while concentration–time data were analyzed for the PK sub-study patients and PK parameters were analyzed for the sub-study cohort only. Relative bioavailability and C_trough, reported as geometric means (GM), were assessed by comparing NVP-XR to NVP-IR.

Statistical analysis

For the PK sub-study, 60 randomized patients were to be entered at selected trial centers, which had experience with PK studies and were equipped in handling PK samples. Of these 60 patients randomized to the PK sub-study, 24 in the NVP-XR and 25 in the NVP-IR groups were included in the analysis.

C_trough (Week 48 and GM of all weeks), AUC_0–24, C_min, and C_max of the XR study formulation were compared with the IR standard formulation using the log-transformed values prior to fitting the data in an analysis of variance (ANOVA) model. The difference between the expected means for log(NVP-XR) − log(NVP-IR) were estimated according to the difference in the corresponding least square means (point estimate), and two-sided 90% confidence intervals were computed based on the t-distribution. These quantities were then back-transformed to the original scale to derive the GM and interval estimates between response under test and response under reference. Descriptive statistics for concentrations at specific time points were calculated only when at least two-third of the individuals had concentrations within the validated concentration range.

Results

Patient demographics

The VERxVE trial population consisted of 1626 screened patients, of whom 1068 received lead-in NVP constituting the treated set. Fifty-five patients discontinued during the lead-in phase. Of 1013 randomized patients, 1011 (NVP-XR: 505; NVP-IR: 506) were treated, which constituted the full analysis set (FAS). Baseline demographic data were similar between non-randomized and randomized patients, and between the NVP-XR and IR groups.¹⁵ The extent of exposure to study medication was similar for both treatment groups.

C_trough by gender, race, and baseline VL stratum

All GM C_trough of patients included in the FAS exceeded 3000 ng/mL and were relatively stable for both formulations during the 48-week period. The NVP-XR C_trough were ~20% lower than those for NVP-IR (Table 1). The NVP-XR to NVP-IR C_trough ratio was 0.77 at Week 48 and 0.82 for the GM of all weeks.

Table 1 Multiple dose NVP C_trough (ng/mL) for NVP-XR 400 mg QD and NVP-IR 200 mg BID

	Week	4	6	8	12	16	24	32	40	48
NVP-XR 400 mg QD	n	418	407	420	423	417	393	385	382	376
	GM	3500	3260	3150	3190	3190	3180	3420	3520	3430
	gCV (%)	52.5	46.1	51.0	54.0	54.5	53.5	48.3	47.4	57.4
NVP-IR 200 mg BID	n	358	352	346	338	345	345	335	321	321
	GM	4220	4070	3950	3950	3980	4120	4120	4250	4460
	gCV (%)	44.1	42.9	52.8	45.2	49.3	46.2	48.0	44.6	46.0
XR/IR GM (%)		82.9	80.1	79.7	80.8	80.2	77.2	83.0	82.8	76.9

Notes: BID, twice daily; C_trough, trough concentration; gCV, geometric coefficient of variance; GM, geometric mean; NVP, nevirapine; NVP-IR, nevirapine immediate release; NVP-XR, nevirapine extended release; QD, once daily.

Female patients in both the NVP-XR (n = 53) and NVP-IR (n = 48) groups had higher C_trough compared to males (n = 273 and n = 323, respectively). Consequently, the NVP-XR to NVP-IR C_trough ratios were slightly higher among female patients (Table 2).

Table 2 C_trough (ng/mL) of NVP-XR 400 mg QD and NVP-IR 200 mg BID by gender, race, and baseline VL strata

	Ctrough^a (ng/mL), GM (gCV%)
	NVP-XR 400 mg BID	NVP-IR 200 mg QD	NVP-XR/NVP-IR GM
Gender
Female	4540 (46.9)	5440 (57.7)	0.84
Male	3280 (57.4)	4310 (42.8)	0.76
Race
Black	4330 (93.8)	5620 (48.8)	0.77
White	3250 (45.8)	4200 (40.4)	0.77
Asian	4040 (43.0)	4370 (20.3)	0.92^b
Baseline VL stratum^c
≤100,000	3480 (62.1)	4410 (46.4)	0.79
>100,000	3350 (48.7)	4550 (45.6)	0.74

Notes: BID, twice daily; C_trough, trough concentration; gCV, geometric coefficient of variance; GM, geometric mean; NVP-IR, nevirapine immediate release; NVP-XR, nevirapine extended release; QD, once daily; VL, viral load.

^a Geometric mean (GM) trough concentration at Week 48

^b Asian group size was too small for fair comparison

^c Baseline values (copies/mL) were calculated as the average of the last two measurements prior to the start of lead-in treatment.

Black patients (NVP-XR, n = 68; NVP-IR, n = 72) showed higher C_trough than white patients (NVP-XR, n = 294; NVP-IR, n = 234) in both the NVP-XR and NVP-IR treatment groups. Black patients tended to have greater variability in C_trough in the NVP-IR group, with a difference of 1310 ng/mL [~30%] between the lowest and the highest concentrations over the 48 weeks for IR compared with a difference of 860 ng/mL for XR. Only a few Asian patients participated in both NVP-XR and NVP-IR treatment groups (15 and 13 patients, respectively), and C_trough for these patients were similar to those of white patients in the NVP-IR group and tended to be higher than those of white patients in the NVP-XR group. The NVP-XR to NVP-IR ratios for black and white patients were mostly comparable (~0.77) (Table 2).

There were no marked differences in C_trough between patients in the two treatment groups based on baseline VL stratum. The NVP-XR to NVP-IR C_trough ratios were also similar for both these patient groups (Table 2).

PK sub-study

Forty-nine patients (NVP-XR: 25; NVP-IR: 24) completed the optional PK sub-study. Plasma concentration-time profiles of NVP on Day 28 showed that mean steady-state plasma concentrations of NVP after oral administration of NVP-XR 400 mg QD exhibited XR characteristics with less fluctuation and were generally lower than those with NVP-IR 200 mg BID (Figure 1). The relative bioavailability of NVP-XR to NVP-IR based on the GM ratio was 0.77 for AUC_0–24 and 0.69 for C_max (Table 3). This is not unexpected since a lower C_max is expected for XR by formulation design, which amounted to 31% lower C_max than that with the IR formulation, whereas the peak-to-trough fluctuation of NVP-XR was 37.5% lower than that with NVP-IR. Individual patient concentration–time profiles showed that the in vivo performance of the NVP-XR tablet formulation was consistently good during multiple dosing, with similar inter-patient variability compared with NVP-IR tablets (% coefficient of variance [%CV] for AUC_0–24, XR: 29.5 and IR: 29.9).

Figure 1 Mean NVP plasma concentration–time profiles after oral administration of NVP-XR 400 mg QD and NVP-IR 200 mg BID on Day 28.

Notes: BID, twice daily; NVP, nevirapine; NVP-IR, nevirapine immediate release; NVP-XR, nevirapine extended release; QD, once daily.

Table 3 Relative bioavailability and adjusted by-treatment GMs of PK sub-study parameters

Parameter	NVP-XR		NVP-IR		Adjusted GM ratio (NVP-XR/NVP-IR); 90% confidence interval
	400 mg QD		200 mg BID
	N	Adjusted GM	N	Adjusted GM
AUC0–24 (ng⋅h/mL)	24	75,323	25	98,176	0.77; 0.65–0.90
Cmin (ng/mL)	24	2581	25	3121	0.83; 0.68–1.01
Cmax (ng/mL)	24	3767	25	5464	0.69; 0.60–0.80

Notes: AUC_0–24, area under the concentration–time curve from zero to 24 h at steady state; BID, twice daily; C_max, maximum concentration at steady state; C_min, minimum concentration at steady state; GM, geometric mean; NVP-IR, nevirapine immediate release; NVP-XR, nevirapine extended release; PK, pharmacokinetic; QD, once daily.

C_trough and efficacy

The effect of C_trough on the proportion of sustained virologic response at Week 48 (defined by two consecutive VL < 50 copies/mL at least 2 weeks apart) was investigated using the GM of all available steady-state C_trough from Week 4 to Week 48 for each patient. There appeared to be no effect of C_trough on the virologic response proportion for patients in the ≥1000 ng/mL group who received NVP-XR 400 mg QD (Table 4). The finding was consistent with use of the minimum steady-state C_trough from Week 4 to Week 48; virologic response rates were comparable between patients in the 1000– <2000 ng/mL and ≥2000 ng/mL trough groups.

Table 4 Proportion of patients with virologic response^a at Week 48 by GM and minimum steady-state NVP C_trough – Full analysis set

	No. with response/total No. (%)
	NVP-IR 200 mg BID	NVP-XR 400 mg QD
Total number of patients	371/463 (80.1)	406/486 (83.5)
GM NVP trough^b (ng/mL)
<1000	1/3 (33.3)	1/5 (20.0)
1000–<2000	8/13 (61.5)	30/37 (81.1)
2000–<3000	50/66 (75.8)	124/143 (86.7)
3000–<4000	115/133 (86.5)	135/156 (86.5)
≥4000	197/248 (79.4)	116/145 (80.0)
Minimum trough_ss^c (ng/mL)
<1000	8/16 (50.0)	30/38 (78.9)
1000–<2000	27/37 (73.0)	126/143 (88.1)
2000–<3000	123/141 (87.2)	133/154 (86.4)
3000–<4000	115/135 (85.2)	74/94 (78.7)
≥4000	98/134 (73.1)	43/57 (75.4)

^a Virologic response was defined using the lower limit of quantification as 50 copies/mL.

^b GM, NVP trough is the geometric mean of steady-state plasma NVP troughs from Week 4 to Week 48

^c Minimum trough_ss is the minimum steady-state trough from Week 4 to Week 48.

Notes: BID, twice daily; C_trough, trough concentration; GM, geometric mean; NVP, nevirapine; NVP-IR, nevirapine immediate release; NVP-XR, nevirapine extended release; QD, once daily.

Discussion

The VERxVE trial demonstrated the non-inferior virologic efficacy and similar safety profile of NVP 400 mg QD, an XR formulation, compared with the standard BID dosing with the currently available IR formulation. An intensive PK sub-study, presented here, was conducted to evaluate further the in vivo performance of the NVP-XR tablets.

It was found that steady-state plasma concentrations of NVP-XR 400 mg QD demonstrated XR characteristics of the XR tablet formulation with comparatively lesser fluctuation and lower overall drug exposure (AUC_0–24 and C_max) in comparison to NVP-IR 200 mg BID. The results showed that NVP-XR tablets performed consistently and reproducibly in individual patients. The relative bioavailability of NVP-XR for steady-state AUC_0–24 and C_max was in good agreement with that found in the previous intensive PK study in HIV-1 patients, albeit C_min was slightly lower in the current study (82.7 vs. 89.6%).¹⁴ There was no indication of dose dumping when medication was taken with or without a meal. When NVP-XR tablets were administered with a high fat breakfast, the relative bioavailability of NVP was higher (~20%) compared with the fasted state. However, the extent of this increase was not clinically relevant¹⁴; therefore, there were no food restrictions in the current study with respect to drug intake.¹⁵

No relationship was noted between the trough NVP concentrations of either the XR or IR formulation and the proportion of patients with a virologic response at least up to a C_trough of 1000 ng/mL. These results were consistent with those for the 2NN study,²⁴ a randomized open-label trial, where the efficacy of 400 mg QD of NVP-IR was compared to 200 mg BID of NVP-IR and to 600 mg QD of efavirenz. These regimens were administered with a fixed antiretroviral background over 48 weeks in treatment-naïve HIV-1 patients.

Several studies have investigated the association of patient demographics such as race, weight, and gender with the PK of NNRTIs. Body weight has been shown to influence plasma NNRTI concentration;²⁰ however, this effect is not consistently seen across studies.¹⁸ Similarly, while clear associations have been reported between ethnicity and concentrations of antiretroviral therapies like NVP or efavirenz in some studies,^18,20 others have found no association between race and antiretroviral therapies.^21,22 In particular, one study by de Maat et al. reported no association between race and the PK of NVP, hence concluding that no race-dependent dose adaptations were required.²² The present study adds to this body of literature, showing no association of NVP PK with race, as the relative trough exposure of NVP-XR to NVP-IR was consistent across the various races.

Although a number of antiretroviral PK studies^19,25 report higher drug exposure in women than in men, there is no clear consensus on whether gender is a significant determinant of NVP concentrations.¹⁹ This study reported higher C_trough in females in both the NVP-XR and NVP-IR groups; however, the XR formulation had no impact on observed gender differences in the PK parameters analyzed. The relative trough exposure of NVP-XR to NVP-IR was also consistent across baseline VL strata.

Taken together, results of this study demonstrate that NVP-XR formulation achieves effective virologic response despite lower C_trough than NVP-IR. NVP-XR, therefore, offers dosing convenience, reduces the pill burden of patients, and may result in increased adherence to antiretroviral therapy. Further, the lower peak-to-trough fluctuations associated with NVP-XR may contribute to increased tolerability. Patients already on NVP-IR can therefore switch to the XR formulation and may benefit from this transition. Eligible treatment-naïve patients may also benefit, despite the 14-day lead-in requirement with NVP-IR to reduce the frequency of hypersensitive reactions.

It must be noted, however, that the use of a parallel study design rather than a crossover design for the intensive PK sub-study may have resulted in limitations to the conclusions that can be drawn from the data. Additionally, the optional nature of the sub-study results in restrictions to the conclusions that can be drawn.

In conclusion, the PK results suggest that QD oral administration of the NVP-XR tablet formulation in HIV-1 patients with background antiretroviral therapy had favorable PK characteristics and was as effective as the IR formulation. Further, the results were not directly affected by demographic factors.

Funding

This study was sponsored and financed by Boehringer Ingelheim Pharmaceuticals, Inc. and funding for editorial assistance for the preparation of the manuscript was provided by Boehringer Ingelheim Pharmaceuticals, Inc.

Declaration of interest

J Gathe has received honoraria for consultancy work, support for travel to meetings, fees for participation in review activities, and payment for writing or reviewing manuscripts and lectures including service on speaker bureaus, from AbbVie, Janssen, Boehringer Ingelheim, Gilead, Merck, GlaxoSmithKline, ViiV Healthcare, Bristol Myers Squibb, and Tibotec. J Mallolas has board membership with and has received payment for lectures from Boehringer Ingelheim, Merck, Janssen, and Gilead. D Podzamczer and B Trottier have received consultancy fees, research grants, and/or payment for lectures from ViiV Healthcare, Pfizer, BMS, Abbott, AbbVie, Gilead, Janssen, and Merck. C Orrell has received an honorarium from Abbott and grants to her institution, Desmond Tutu HIV Foundation. G Knecht received an honorarium and payment for the development of educational presentations from Infektio Research.

W Zhang, JP Sabo, R Vinisko, M Drulak, and AM Quinson are employees of Boehringer Ingelheim. CL Yong was an employee of Boehringer Ingelheim at the time of the study and is currently retired.

Contributors

All the authors have contributed to conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, and provided final approval of the manuscript.

Acknowledgments

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. The authors received no direct compensation related to the development of the manuscript. Writing, editorial support, and formatting assistance were provided by Michelle Rebello, PhD, of Cactus Communications and Ghzaleh Masnavi and Amineh Zafarani of Euro RSCG Life. Both were contracted and compensated by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

The authors wish to thank the patients, investigators, clinicians, and nursing staff who participated in the trial. We thank co-investigator Dr. Maria Martinez-Rebollar for her contribution to the study.