The Steady-State Pharmacokinetics of Nelfinavir in Combination With

Home , Nelfinavir

Antiviral Therapy 10:349–355 The steady-state pharmacokinetics of nelfinavir in combination with tenofovir in HIV-infected patients Guido Kruse1, Stefan Esser 2, Hartmut Stocker 3,4, Antje Breske1, Andreas Koerber 2, Maija Kopperman2, Heidi Wiehler 2, Birgit Ross2, Christiane Möcklinghoff 5, Andrew Hill 6, Mark Becker7 and Michael Kurowski1,4*

1Therapia GmbH, Berlin, Germany 2University of Essen, Essen, Germany 3Auguste Viktoria Hospital, Berlin, Germany 4German HIV/AIDS Competence Network, Germany 5Roche, Grenzach, Germany 6University of Liverpool, Liverpool, UK 7Roche, Basel, Switzerland

*Corresponding author: Tel: +49 30 7903 3920; Fax: +49 30 7903 3922; E-mail: [email protected]

Background: The nucleotide analogue, tenofovir, has spectrometry for nelfinavir, its primary metabolite, M8, been shown to lower plasma atazanavir levels in pharma- and tenofovir. The parameters AUC0–12, C0, Cmax and Tmax cokinetic trials, an interaction that may be partly were compared for nelfinavir with and without tenofovir reversed by the addition of ritonavir, whereas plasma by calculating geometric mean ratios (GMRs) of the tenofovir levels are themselves raised when the drug is pharmacokinetic parameters with associated 95% confi- combined with lopinavir/ritonavir. dence intervals (95% CIs). Safety was assessed Objective: To investigate the effect of tenofovir coadmin- throughout the study. istration on the steady-state pharmacokinetics of Results: The addition of tenofovir to the nelfinavir-based nelfinavir in HIV-infected patients. regimen had no effect on the pharmacokinetics of nelfi-

Methods: Eighteen patients received nelfinavir 1250 mg navir. The GMR of the nelfinavir AUC0–12 values was 0.97 twice daily plus prescribed nucleoside reverse transcrip- (95% CI: 0.80–1.17). There was a slight decrease in M8 tase inhibitors for at least 14 days, with pharmacokinetic metabolite (AUC0–12 ratio, 0.87; 95% CI: 0.68–1.11) but measurements performed on day 15. Treatment with this was not significant. No serious adverse events nelfinavir was continued for another 7 days with the occurred through the study period. addition of 300 mg tenofovir once daily. Pharmacokinetic Conclusion: Nelfinavir does not require dose adjustment measurements were repeated on day 22. Plasma samples when coadministered with tenofovir and appears to be were analysed by liquid chromatography–tandem mass well-tolerated by HIV-infected patients.

Introduction

Several pharmacokinetic (PK) interactions have been were themselves raised when the nucleotide analogue described between the nucleotide analogue tenofovir was combined with ritonavir-boosted lopinavir [4]. The disoproxil fumarate, the orally bioavailable prodrug of unpredictability of these tenofovir-associated interac- tenofovir, and other antiretroviral agents, including tions, together with the popularity of tenofovir as an protease inhibitors (PIs) [1]. As tenofovir is eliminated antiretroviral agent, necessitates careful examination of predominantly by the renal route [2] and PIs are exten- the steady-state pharmacokinetics of antiretroviral sively metabolized in the liver, the mechanisms agents that might be coadministered with it. underlying these interactions are unclear. It has been Nelfinavir-based highly active antiretroviral therapy suggested, however, that these interactions might occur (HAART) has demonstrated potent and durable viro- at the drug absorption stage [3]. Recently, it was shown logical control of HIV for at least 4 years [5–7]. Data that tenofovir leads to a reduction in exposure to from large, randomized clinical trials show nelfinavir to concomitantly administered atazanavir, which is consis- have comparable efficacy with more recently developed tent with a significant interaction between tenofovir PIs, such as atazanavir and ritonavir-boosted fosampre- and this new PI [3]. Conversely, plasma tenofovir levels navir [8–11], as well as a good tolerability and safety

profile, which is characterized by low rates of toxicity to the recent versions of both the German and and treatment-related discontinuations [7]. In addition, European Guidelines for Good Clinical Practice. the absence of mutations at failure or the selection of the unique D30N resistance pathway by nelfinavir- Study design based regimens may allow the subsequent successful use This prospective Phase I trial was a single-centre, open- of a boosted PI [12–15]. Furthermore, nelfinavir label, multiple-dose, single-group study. The study remains the only commercially available PI that is not design is shown in Figure 1. routinely combined with boosting doses of ritonavir, After a pre-study phase of at least 14 days with and as the interaction with tenofovir appears more orally administered nelfinavir 1250 mg twice daily pronounced with unboosted atazanavir, investigation of (Viracept® 5×250 mg tablets) + two nucleoside reverse the effect of tenofovir on nelfinavir pharmacokinetics transcriptase inhibitors (NRTIs), PK measurements was warranted. were performed at day 15. The patients then continued taking this regimen for a further 7 days (investigational Methods phase) whilst also receiving oral tenofovir 300 mg once daily (Viread® 1×300 mg tablets). On day 22, PK Study population measurements were repeated and on day 23 pre-study HIV-infected patients over the age of 18 were eligible dosing resumed if deemed appropriate by the investi- for this study if they were taking a nelfinavir- gator. A follow-up examination was conducted within containing regimen, with nelfinavir dosed at 1250 mg 14 days of this second PK assessment. twice daily for at least 14 days prior to study entry, The course of the study period was identical for each had no significant clinical and laboratory findings patient enrolled. A pre-study examination was carried during pre-study screening and were able to provide out 2–14 days prior to enrolment into the investiga- written consent to comply with study requirements. tional phase. Medical history was recorded and a Patients were excluded if they had any history or clin- physical examination was conducted. Vital signs and ical findings that might interfere with the body temperature were measured, and blood and urine pharmacokinetics of the study drugs, if they had sampled for routine laboratory parameters. received any investigational drug within 3 months prior Safety was assessed throughout the study. Subjects to the start of the study, if they had a recent (≤3 years) were asked whether they had experienced any adverse history of active substance abuse or were intolerant to events (AEs) on days 15 and 22 and at the follow-up any of the study drugs. Patients were also excluded if visit. Repeat laboratory tests were carried out on day they had received any co-medication judged likely to 22 and during the follow-up visit; physical examina- interfere with nelfinavir or tenofovir (such as known tion was repeated at follow-up. inducers/inhibitors of the CYP3A4 enzyme) in the 2 weeks prior to study entry. Blood sample collection and preparation The study was conducted in accordance with the Patients were required to keep a journal recording their principles of the Declaration of Helsinki and adhered compliance to the study regimen and the two doses of

Figure 1. Study design

Pharmacokinetic Pharmacokinetic Follow-up Pre-study measurement Investigational measurement within phase day 1 phase day 2 14 days

Subjects Subjects Resume admitted to admitted to pre-study unit unit therapy

Plus tenofovir 300 mg once daily

Nelfinavir 1250 mg twice daily

1–14 15 16 21 22 23> Days

study drugs prior to PK sampling were observed. On These PK parameters were also determined for days 15 and 22, patients were admitted to the study tenofovir on day 22. All pharmacokinetic parameters unit for PK sampling. On both of these occasions were analysed descriptively including arithmetic mean, blood samples were collected for the determination of standard deviation, geometric mean, minimum, plasma concentrations of nelfinavir, the nelfinavir maximum and median. The nelfinavir concentration– metabolite M8 (nelfinavir hydroxy-t-butylamide) and, time profiles at day 15 and day 22 were compared by if appropriate, tenofovir, using identical sampling calculation of geometric mean ratios (GMRs) for the schedules on days 15 and 22. Blood samples (3 ml) log transformed AUC0–12 and Cmax including 95% were drawn 15 min prior to dosing (time 0), then at 1, confidence intervals (95% CI). 2, 3, 4, 6, 8, 10 and 12 h post-dose. All samples were centrifuged within 1 h of collection and plasma trans- Results ferred immediately to a –20°C freezer for storage until analysis. Patient demographics Nineteen patients undergoing long-term nelfinavir- Analytical methods containing treatment for HIV infection underwent The analytical method for the determination of plasma pre-study screening. Of these 19, six failed to complete concentrations of the tenofovir metabolite 9-[2-(R)- the study according to the protocol: one refused to (phosphonomethoxy)propyl]adenine (PMPA) has continue, two continued to take nelfinavir according to recently been developed and fully validated by the a three times daily dosing schedule, two were found to authors. In brief, 0.1 ml of serum was extracted with have taken nevirapine and one had taken simvastatin, acetonitrile (0.5 ml) and centrifuged. The supernatant which, as substrates of CYP3A4, may interact phar- was removed and reduced under vacuum to approxi- macokinetically with nelfinavir. Baseline demographics mately 0.05 ml, to which 0.1 ml of the aqueous chro- for the 13 patients who met study criteria are presented matographic eluent was added, and the resulting in Table 1. solutions stored at –25°C prior to drug analysis. During the study, all subjects who met study criteria Thawed samples were chromatographed on a Luna had a physician-selected NRTI backbone consisting of C18 HPLC column (Phenomenex, Torrance, CA, USA) two of the following: lamivudine (n=11), zidovudine using gradient elution. The aqueous mobile phase was (n=7), stavudine (n=6), didanosine (n=1) and abacavir 5 mM ammonium acetate buffered to pH 7.5 with (n=1). Baseline antiretroviral medication was maintained ammonia, and the organic phase was acetonitrile unchanged throughout the study. The only other containing 0.1% formic acid. An API 3000 mass spec- concomitant medication taken by more than two patients trometer (Applied Biosystems, Streetsville, ON, at any time during the study was pravastatin (n=3). Canada) equipped with an ESI interface and run with Analyst 1.2 software was used for peak detection, inte- Pharmacokinetic analyses gration and quantification. Quantification of PMPA Data are presented for all 13 patients who met study was achieved by reference to the internal standard 2- criteria. Geometric mean concentration–time profiles chloroadenosine (Sigma, St Louis, MO, USA). for nelfinavir and M8 are shown in Figures 2 and 3, Concentrations of nelfinavir and M8 were quantified respectively. During the first PK sampling period (study by liquid chromatography–tandem mass spectrometry day 15, without tenofovir), prior to dosing with nelfi-

(LC/MS/MS) according to a validated method [16]. navir 1250 mg, the geometric mean C0 was The lower limits of quantification were 33 ng/ml for 1358 ng/ml. Concentrations increased over the next nelfinavir, 38 ng/ml for M8 and 78 ng/ml for PMPA. few hours, reaching a geometric mean Cmax of 3753 The precision (% CV) of the assay was within the acceptable range of ±15% for all three compounds. Table 1. Baseline characteristics of study population Pharmacokinetic and statistical methods Mean (range)* n=13† Based on the plasma concentration data, the following model-independent pharmacokinetic parameters were Gender, male/female, n (%) 8/5 (62/38) determined for nelfinavir and M8 on days 15 and 22 Age, years 49 (36–72) (that is, in the absence and presence of tenofovir, Body mass index, kg/m2 24 (19–36) respectively): area under the plasma concentration– CD4 cell count, cells/mm3 562 (199–1310) ‡ time curve from time 0–12 hours (AUC0–12) computed HIV viral load, copies/ml NA (<50–2927) using the linear-log trapezoidal rule, plasma concentra- *Unless otherwise specified. †Baseline CD4 cell count and viral load only avail- tion observed at time 0 (C0), maximum observed able for 12 patients. ‡Mean viral load not available as seven out of 12 patients plasma concentration (Cmax), and time to Cmax (Tmax). had undetectable viral load (<50 copies/ml) at baseline.

Antiviral Therapy 10:2 351 G Kruse et al.

Figure 2. Geometric mean 12-h nelfinavir plasma concentration–time profiles for nelfinavir 1250 mg twice daily, administered with (day 22) and without (day 15) tenofovir 300 mg once daily (n=13)

5000 NFV concentration without TDF NFV concentration with TDF

4000

3000

2000

1000 Geometric mean NFV concentration, ng/ml

0 0 2 4 6 8 10 12 Time, h

NFV, nelfinavir; TDF, tenofovir.

Figure 3. Geometric mean 12-h M8 plasma concentration–time profiles for nelfinavir 1250 mg twice daily, administered with (day 22) and without (day 15) tenofovir 300 mg once daily (n=13)

2500 M8 concentration without TDF M8 concentration with TDF

2000

1500

1000

500 Geometric mean M8 concentration, ng/ml

0 0 2 4 6 8 10 12 Time, h TDF, tenofovir.

Table 2. Nelfinavir and M8 PK parameters [expressed as geometric means and GMRs* (with 95% CIs)] for nelfinavir 1250 mg twice daily administered with (day 22) and without (day 15) tenofovir 300 mg once daily (n=13)

Without TDF day 15 With TDF day 22 GMR day 22/day 15

NFV

AUC0–12, ng·h/ml 28 830 (21 300–39 010) 27 700 (20 530–37 360) 0.97 (0.80–1.17)

Cmax, ng/ml 3753 (2892–4872) 3729 (2841–4895) 0.99 (0.80–1.24)

C0, ng/ml 1358 (768–2402) 1390 (882–2189) 1.02 (0.66–1.58)

Tmax, h 4 (3–6) 3 (1–8) 0.65 (0.37–1.15) M8

AUC0–12, ng·h/ml 8392 (4808–14 650) 7301 (4432–12 030) 0.87 (0.68–1.11)

Cmax, ng/ml 1261 (718–2214) 1076 (620–1864) 0.85 (0.68–1.11)

C0, ng/ml 370 (161–850) 356 (198–641) 0.96 (0.65–1.11)

Tmax, h 5 (4–7) 3 (1–10) 0.63 (0.36–1.12)

*The geometric mean ratio (GMR) compares PK values across the two study days. A GMR of 1 means no change in drug levels; a GMR of 2 means a 100% rise in drug levels. If the confidence intervals (CIs) of the GMRs include 1 then the change is not statistically significant. NFV, nelfinavir; TDF, tenofovir.

after 4 h. Subsequently, levels of nelfinavir declined Table 3. Tenofovir PK parameters [expressed as geometric over 8 h and measured 1414 ng/ml at the end of the means (with 95% CIs)] for tenofovir 300 mg once daily 12-h dosing interval. PK profiles of the M8 metabolite administered with nelfinavir 1250 mg twice daily (n=15) exhibited a similar time course. Geometric mean C0 Tenofovir With nelfinavir day 22 was 370 ng/ml, representing 27.2% of the corresponding nelfinavir concentration, with a Cmax of AUC0–12, ng.h/ml 2899 (1965–4277)

1261 ng/ml observed after 5 h. During the elimination Cmax, ng/ml 499 (323–770) phase, the M8 concentrations decreased to 436 ng/ml C0, ng/ml 111 (85–144) after 12 h. For both compounds, similar profiles were Tmax, h 2 (1–2) obtained on day 22 following 7 days of tenofovir coadministered with the same dose of nelfinavir. Nelfinavir concentrations started at 1390 ng/ml, reached maximum values of 3729 ng/ml after 3 h and declined to 1279 ng/ml after 12 h. The respective geometric for PMPA was found to be 111 ng/ml. A Cmax of mean concentration of the M8 metabolite was found to 499 ng/ml was observed after 2 h, with a final concen- be 356 ng/ml at time 0, reaching a Cmax of 1076 ng/ml tration of 147 ng/ml observed 12 h post-dose. after 3 h before falling to a final concentration of 390 ng/ml after 12 h. Nelfinavir’s geometric mean Safety

AUC0–12 for the observed 12-h dosing interval was There were no serious AEs and no deaths during the found to be 28 830 ng·h/ml without tenofovir and study. Amongst the 18 patients who completed the 27700 ng·h/ml with tenofovir, respectively. The corre- study, there were a total of 10 AE episodes reported sponding values for the M8 metabolite were during the tenofovir coadministration (investigational) 8392 ng·h/ml and 7301 ng·h/ml, in the absence and phase. All were mild to moderate in nature and none presence of tenofovir, respectively. resulted in discontinuation. Of these, four AE episodes, The PK parameters measured for nelfinavir and M8 rated as mild, were deemed possibly related to study on days 15 and 22, in the absence and presence of medication: nausea (2 episodes), diarrhoea (1) and tenofovir, respectively, are compared in Table 2. None dysgeusia (1). of the primary test parameters showed a significant difference when comparing periods with and without Discussion coadministration of tenofovir by calculation of GMRs with 95% CIs. The use of combination antiretroviral therapy has led to PK parameters for PMPA, the active metabolite of marked reductions in the morbidity and mortality asso- tenofovir, were analysed during the second PK ciated with HIV/AIDS [17]. However, inherent in the sampling study period only (study day 22), in the pres- use of these necessarily complex antiretroviral combi- ence of nelfinavir, and are shown in Table 3. The nations is the risk of drug–drug interactions and their geometric mean concentration–time profile for PMPA subsequent effect on optimal drug exposure. While is shown in Figure 4. The geometric mean of C0 values interactions between concomitantly administered

Antiviral Therapy 10:2 353 G Kruse et al.

Figure 4. Geometric mean 12-hour PMPA plasma concentration–time profile for tenofovir 300 mg once daily administered with nelfinavir 1250 mg twice daily (day 22) (n=13)

700

600

500

400

300

PMPA concentration, ng/ml PMPA 200

100

0 0 2 4 6 8 10 12 Time, h

antiretrovirals can sometimes prove beneficial, as with The aim of the present study was to investigate the the use of low-dose ritonavir to boost drug plasma effect of tenofovir (300 mg once daily) coadministration levels of a coadministered PI, negative interactions may on the steady-state pharmacokinetics of nelfinavir reduce drug levels to a point where they are no longer (1250 mg twice daily) in HIV-infected patients. The sufficient and virological control is lost. In order to results showed that the addition of tenofovir to a achieve optimal regimens it is therefore important that nelfinavir-based treatment regimen had no effect on the any interactions are fully understood. Reports of the pharmacokinetic parameters of nelfinavir. The GMR potential for drug–drug interactions with tenofovir of nelfinavir AUC values comparing exposure in the have spurred PK interaction studies of existing licensed absence and presence of tenofovir was 0.97 (95% CI: antiretrovirals with this agent. 0.80–1.17). Similarly there was no difference in C0 for The pharmacokinetics of nelfinavir after multiple nelfinavir regardless of whether tenofovir was coad- dosing are different from those after single-dose ministered or not (GMR 1.02; 95% CI: 0.66–1.58). A administration [6,18]. Following multiple-dose admin- slight decrease in exposure to the M8 metabolite was istration, nelfinavir has been found to induce its own noted, but this was not statistically significant (AUC metabolism. Nelfinavir levels reach steady state after GMR 0.87; 95% CI: 0.68–1.11). Again, there was no approximately 1 week and have been found to be significant difference in the M8 C0 values (C0 GMR slightly lower than after single-dose administration 0.96; 95% CI: 0.65–1.11). [19]. The pharmacokinetics after single-dose adminis- This study was not designed to assess the effect of tration have not been helpful in predicting steady-state nelfinavir on tenofovir, so tenofovir parameters can pharmacokinetics of nelfinavir. It is therefore necessary only be compared with historical controls, which has to evaluate drug interactions after steady state has been well-described limitations. In this study, the mean reached for nelfinavir. Given that the elimination half- pharmacokinetic results for tenofovir were slightly life of tenofovir is 17 h [20], it was felt that an investi- greater than previously reported [20]. This study also gational phase of 7 days – the equivalent of 10 demonstrated that the combination of nelfinavir and half-lives – should be sufficient to ensure steady-state tenofovir was not associated with any new safety or conditions for this drug. tolerability issues, at least in the short term.

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Received 8 November 2004, accepted 24 December 2004

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