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Antimicrobial Agents and Chemotherapy, December 2002, p. 3877-3882, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3877-3882.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Coadministration of Indinavir and Nelfinavir in Human Immunodeficiency Virus Type 1-Infected Adults: Safety, Pharmacokinetics, and Antiretroviral Activity

University of Pittsburgh, Pittsburgh, Pennsylvania,¹ University of California-San Diego, San Diego,² Agouron Pharmaceuticals, La Jolla, California,⁴ University of Alabama at Birmingham, Birmingham, Alabama,³ Merck Research Laboratories, West Point, Pennsylvania⁵

Received 28 January 2002/ Returned for modification 5 May 2002/ Accepted 12 August 2002

	ABSTRACT

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Combinations of protease inhibitors (PIs) can have potentially beneficial pharmacokinetic interactions, resulting in higher drug levels and less frequent dose administration. Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and are commonly prescribed antiretroviral agents. Pilot pharmacokinetic data suggested a bidirectional enhancing interaction between IDV and NFV. A phase II study was conducted to evaluate the safety, pharmacokinetics, and antiviral activity of IDV plus NFV given in a combination every 12 h in HIV-1-infected subjects. IDV plus NFV was given as a twice-daily regimen to 20 HIV-1-infected subjects who were PI naive (11 of 20 were antiretroviral naive). After week 18, nucleoside reverse transcriptase inhibitors were added to the treatment regimen in seven subjects. The enrolled subjects had a geometric mean baseline plasma HIV-1 RNA of 63,095 copies/ml and a mean CD4⁺ cell count of 266 cells/mm³. Pharmacokinetic evaluations were performed at the following doses: IDV at 1,000 mg every 12 h (q12h) plus NFV at 750 mg q12h, IDV at 1,000 mg q12h plus NFV at 1,000 mg q12h, and IDV at 1,200 mg q12h plus NFV at 1,250 mg q12h. The coadministration of IDV plus NFV resulted in a modest inhibition of IDV elimination, resulting in a plasma profile of IDV 1200 mg q12h (with NFV at 1,250 mg q12h) that was comparable to the standard IDV dose of 800 mg q8h. In contrast, IDV had no apparent effect on the pharmacokinetic profile of NFV. The combination of IDV and NFV was generally well tolerated and resulted in sustained virologic suppression with 45% of the subjects having an HIV-1 RNA level in plasma of <400 copies/ml at week 72 (intent-to-treat).

	INTRODUCTION

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Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that when used in a combination regimen produce marked and durable reductions in HIV-1 RNA levels in treated patients (4, 5, 7). Although protease inhibitors (PIs) are commonly prescribed individually in combination with nucleoside reverse transcriptase inhibitors (NRTIs), the evaluation of regimens with two or more PIs has progressed for several reasons. First, combinations of PIs can have potentially beneficial pharmacokinetic interactions such as higher drug levels (1). Second, these pharmacokinetic interactions allow for less-frequent dose administration and reduced dietary restrictions that may lead to improved adherence (2). Finally, combinations of PIs may have increased potency as a result of complementary resistance profiles and enhanced activity against viral quasispecies.

This study describes the results of a multiple-dose (steady-state) analysis that was designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the IDV plus NFV combination given every 12 h (q12h) to HIV-1-infected patients. Although at present dual PIs are usually administered in combination with NRTIs, the present study was conducted at a time when combinations of dual PI therapy used alone were undergoing evaluation in several clinical trials. This PI combination was chosen because of preliminary data that demonstrated bidirectional enhancement of NFV and IDV levels in healthy volunteers. In that pilot pharmacokinetic study (Agouron Pharmaceuticals, Viracept package insert), the administration of NFV at 750 mg q8h for 7 days increased the mean IDV area under the concentration-time curve in plasma (plasma AUC) of a single 800-mg dose by ca. 51%. Conversely, the administration of IDV at 800 mg q8h for 7 days increased the mean NFV plasma AUC for a single 750-mg dose by ca. 83%. Based on these findings, it was anticipated that chronic coadministration of IDV plus NFV would result in mutual inhibition of drug clearance and thereby allow lower doses and/or a reduced frequency of dosing for one or both drugs.

	MATERIALS AND METHODS

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Study subjects. Male and female subjects with HIV-1 infection were enrolled at three study sites. Eligible subjects had CD4⁺-cell count of 100 cells/mm³ and levels of HIV-1 RNA in plasma of >30,000 copies/ml within 60 days of treatment initiation.

Pregnant or lactating women were not enrolled. All women of childbearing potential had a negative serum pregnancy test within 10 days prior to enrollment in the study. All subjects agreed to use accepted contraceptive methods (including barrier) for the duration of the study. Additional exclusion criteria included prior treatment with any HIV-1 PI, the use of chronic therapy for an active opportunistic infection or any malignancy, and the use of any investigational agents, including unlicensed antiretroviral agents.

The study was approved by the institutional review board at each site, and all subjects provided written informed consent prior to study entry and with each study modification.

Study design: part I. This protocol was a phase II, parallel, time-lagged, two-panel multiple-dose study (Table 1) in which subjects received IDV at 1,000 mg q12h in combination with NFV at 500 mg q12h or at 750 mg q12h in a placebo-controlled lead-in period of 2 to 4 weeks. This lead-in period was used to assess the safety of this new combination. The study was enrolled between April and September 1997. At week 4, all subjects received open-label IDV at 1,000 mg q12h and NFV at 750 mg q12h. Weekly visits for safety assessments were conducted for the first 4 weeks, and all subjects had pharmacokinetic evaluation on day 29. Subjects were instructed to take the study medications orally with a light meal, which was also used during the pharmacokinetic evaluation, and to maintain adequate hydration by drinking 48 oz. (1,440 ml) of water daily. The study medications were supplied as 200-mg IDV capsules and 250-mg NFV tablets with matching placebos (obtained from Merck & Co., Inc., West Point, Pa., and Agouron Pharmaceuticals, La Jolla, Calif., respectively).

Pharmacokinetic sampling. Subjects were admitted to the clinical research unit on the evening of day 28. All antidiarrheal medications were discontinued for 24 h prior to the beginning of pharmacokinetic sampling until its completion. On day 29, the morning dose of medications was taken after a standardized light breakfast. Blood samples for NFV were collected predose; at 30 min; and at 1, 2, 3, 4, 5, 6, 8, 10, and 12 h. Blood samples for IDV were collected predose; at 15, 30 and 45 min; and at 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 h. Blood samples were collected in heparinized Vacutainer tubes and were centrifuged immediately at 3,500 rpm for 10 min at 4°C. The plasma fraction was removed and stored at -20°C until analyzed.

Clinical monitoring. Subjects were seen weekly for 4 weeks then every 4 weeks for the duration of the study. At each study visit, the following evaluations were performed: physical examination; adverse experiences history; blood and urine for safety, including complete blood count, serum chemistries (sodium, potassium, creatinine, urea, glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, direct and indirect bilirubin, triglycerides, and amylase), and urinalysis; CD4⁺-cell count; and quantitative HIV-1 RNA (Roche Amplicor Assay and Roche Ultrasensitive Assay). Serum pregnancy tests were performed prior to study treatment and every 4 weeks thereafter for all women with child-bearing potential. A final visit was conducted 2 weeks after the discontinuation of study therapy, including physical examination and safety laboratory evaluations.

Assays for drug levels in plasma. Concentrations of NFV and the active metabolite AG1402 in plasma were assayed by high-performance liquid chromatography with UV detection as previously described (6, 8).

IDV concentrations were determined by liquid chromatography tandem mass spectrometry (LC/MS/MS). Briefly, IDV and the internal standard were isolated from plasma samples by a single-step liquid-liquid extraction with methyl-t-butyl ether. The chromatographic separation was accomplished on a Zorbax 300SB-C₁₈ column with a mobile phase of acetonitrile-ammonium acetate aqueous solution. Analytes were detected and quantified by MS/MS by using an electrospray interface. The method was selective in determining the concentrations of IDV in plasma from patients receiving combination treatment with IDV and NFV. The absence of potential interference from NFV was confirmed by comparison of the peak area of analyte from spiked control plasma and spiked plasma from a patient dosed with NFV alone. The plasma assay was validated in the linear range of 5 to 2,000 ng/ml. Part I of the study was supported by an assay utilizing cation-exchange solid-phase extraction by using SCX cartridges (10) by using the same LC/MS/MS conditions as described above.

Pharmacokinetic analysis. Steady-state pharmacokinetic parameters estimated from the day 29 assessments included the maximum observed concentration in plasma (C_max), the time at which C_max was observed (t_max), the 12-h postdose trough concentration (C_min), and AUC over the 12-h dose interval. AUC values were estimated by using the linear trapezoidal method (9). To facilitate comparison of AUC values to those from historical thrice-daily (IDV) or twice-daily (NFV) regimens, the AUC values were converted to 24-h AUC values (AUC_0- x doses/day)

Statistical analysis. Continuous data were summarized by using descriptive statistics. Baseline values for CD4⁺-cell count and HIV-1 RNA levels in plasma were the mean of two values obtained during the screening period prior to the initiation of study treatment. Adverse events were graded according to the Division of AIDS (National Institutes of Health) toxicity table. The following three methods were applied to estimate the proportion of subjects who had HIV-1 RNA levels in plasma of <400 copies/ml (which is also defined as failure): (i) the observed method, which used only the observed data at each time point and ignored the dropout information; (ii) the "noncompleter = failure" method, which used the observed data at each time point and counted all subjects who withdrew as treatment failures after they discontinued therapy regardless of the reasons for withdrawal; and (iii) the generalized estimation equation (GEE) model-based method, which treated subjects as treatment failures after dropout if they discontinued therapy due to therapeutic failure. In the GEE approach, missing values were assumed to be <400 copies/ml if both the immediately preceding and succeeding HIV-1 RNA levels were <400 copies/ml. A corresponding rule was applied if both values were 400 copies/ml. Other missing values, including those subsequent to discontinuation for reasons not known to be therapy related, were left as missing. The GEE model-based method is the primary approach.

The same three methods were applied to estimate the proportion of subjects with HIV-1 RNA levels at <50 copies/ml, assuming that the HIV-1 RNA levels of >400 copies/ml from the Amplicor assay were also >50 copies/ml from the UltraSensitive assay. Data from the first 3 weeks and the first 4 weeks were excluded from the GEE approach for the proportions with HIV-1 RNA of <400 and <50 copies/ml, respectively. These data were excluded since the response rates were zero and the GEE method did not provide estimates for those time points.

Changes from baseline in CD4⁺-cell counts and in log₁₀ HIV-1 RNA levels were estimated by mixed effects models. Missing values for subjects who discontinued therapy due to therapeutic failure were handled by the last observation carrying forward method after dropout. For comparison purposes, the mean changes of CD4⁺-cell counts and HIV-1 RNA levels, based only on observed data, were also calculated.

	RESULTS

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Study patients. Twenty-one subjects were enrolled in the present study at three clinical sites. One subject (AN4159) was excluded from all analyses (except for safety) due to the inability to remain on protocol therapy due to rash and back pain as described in the safety evaluation section. The remaining 20 subjects were male with a median age of 38.5 years (range, 23 to 60 years). Seventy percent (14 of 20) were Caucasian, and thirty percent (6 of 20) were black. The geometric mean baseline HIV-1 RNA level in plasma was 63,095 copies/ml, and the mean baseline CD4⁺ cell count was 266 cells/mm³ (range, 101 to 568). Fifty-five percent (11 of 20) of subjects were antiretroviral naive at study entry; the remaining 9 subjects had been previously treated with NRTIs only.

Pharmacokinetic evaluations were completed for parts I, II, and III in 11, 12, and 11 subjects, respectively. Seven subjects completed all three pharmacokinetic evaluations.

Pharmacokinetic evaluation. (i) IDV. The IDV and NFV pharmacokinetic parameters of the three dosing combinations are summarized in Table 2 and Table 3, respectively. With the initial dosing combination of IDV at 1,000 mg q12h plus NFV at 750 mg q12h, the IDV C_min (mean, 205 nM; 1 µM = 0.61381 mg/liter) was lower than that seen historically with standard IDV at 800 mg q8h without NFV (mean, 251 nM); however, the estimated AUC_0-24 and C_max were comparable (Merck & Co. [Crixivan package insert]). The administration of NFV at 1,000 mg q12h had no additional effect on the IDV pharmacokinetics compared to NFV at 750 mg q12h. Concomitant IDV at 1,200 mg q12h and NFV at 1,250 mg q12h resulted in C_max, AUC_0-24, and C_min values comparable to those achieved with IDV at 800 mg q8h without NFV (Fig. 1). The dose of NFV did not affect the IDV t_max values, which were 1.7 ± 0.8, 1.8 ± 0.7, and 2.1 ± 1.2 h for the 750-, 1,000-, and 1,250-mg doses of NFV, respectively.

View larger version (27K): [in this window] [in a new window]   FIG. 1. Mean concentrations of IDV in plasma at steady-state after combination administration of IDV with various doses of NFV.

View larger version (21K): [in this window] [in a new window]   FIG. 2. Mean concentrations of NFV in plasma at steady-state after combination administration of IDV with various doses of NFV.

Figure 3 exhibits the proportion of subjects with HIV-1 RNA levels in plasma below the limit of quantification (400 copies/ml) of the Amplicor assay (Fig. 3A) and below the limit of quantification (50 copies/ml) of the UltraSensitive assay (Fig. 3B). At week 72, 9 of 11 subjects (81.1%) who had an Amplicor assay result showed HIV-1 RNA levels in plasma of <400 copies/ml. Among the 11 subjects, 7 (63.3%) had their HIV-1 RNA levels of <50 copies/ml. From the "noncompleter = failure" approach, the percentages of subjects with HIV-1 RNA levels of <400 and of <50 copies/ml were 45 and 35%, respectively, at week 72. The corresponding estimates from the GEE model-based approach were 57.2% (95% confidence interval [CI] = 34.0 to 77.6%) and 45.5% (95% CI = 24.3 to 68.5%), respectively, at week 72.

View larger version (46K): [in this window] [in a new window]   FIG. 3. Proportion of patients with HIV-1 RNA levels of <400 and <50 copies/ml. The bars indicate the 95% CI values.

Safety. The coadministration of IDV and NFV was generally well tolerated. The most common (incidence, >20%) side effects of greater than or equal to grade 2 were gastrointestinal symptoms with five subjects (24%) experiencing diarrhea, and five subjects (24%) reporting nausea. The diarrhea was moderate in all cases except one subject who had a single episode of severe diarrhea. None of the subjects discontinued study therapy due to gastrointestinal side effects. Two subjects developed clinical symptoms of nephrolithiasis, one of whom experienced two episodes, while the other, who had a past medical history of nephrolithiasis, experienced mild right flank pain and nausea on day 2 of therapy. The patient was treated in the emergency department and released. He remained symptom-free until he was lost to follow-up at week 18. The patient who experienced two episodes of nephrolithiasis at study weeks 18 and 33 required hospitalization after the second episode, and a ureteral stent was placed. The stent was removed, and the subject recovered. For both subjects, the episodes of nephrolithiasis were felt by the investigators to be related to study therapy. One subject experienced a grade 3 rash on day 25. All study therapy was held until resolution of the rash, at which time the investigator started the subject on IDV at 800 mg q8h only. The subject then experienced back pain (grade 2) and discontinued IDV due to suspected nephrolithiasis. The subject was given NFV 750 mg three times daily without recurrence of the rash. Because the subject was not taking medications per protocol, AN4159 was included only in the safety analysis for this report. No serious laboratory adverse events were observed in the present study.

	DISCUSSION

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In this study of HIV-infected patients, concomitant administration of IDV plus NFV resulted in a modest inhibition of IDV elimination, a finding that was consistent with the single-dose study. This modest inhibitory effect of NFV on IDV resulted in a plasma profile for IDV (C_max, AUC, and C_min) that was similar for a reduced dose frequency (IDV at 1,200 mg every 12 h in the presence of NFV) versus the standard IDV regimen of 800 mg every 8 h. However, in contrast to the single-dose results, IDV had no obvious effect on the pharmacokinetic profile of NFV during multiple-dose coadministration in the current study.

A similar discordance between single-dose and multiple-dose drug interactions for NFV has been observed in other NFV studies despite a lack of notable systemic accumulation of NFV between single-dose and steady-state (i.e., discordance not attributable to differing NFV concentrations in plasma) (Agouron Pharmaceuticals, unpublished data). Several explanations can be proposed to explain this finding. First, NFV has been observed to have both inhibition and induction effects on drug-metabolizing enzymes. The resulting net effect of an interaction on NFV and/or the concomitant drug may differ depending on whether a study employs NFV single-dose administration, where inhibition may occur but not induction or autoinduction, or multiple-dose administration where both inhibition and induction occurs. Thus, the inhibitory effect of IDV on a single-dose of NFV may become diminished or negligible during NFV multiple dosing when a counterbalancing NFV autoinduction takes place. Another potential reason may be that IDV is a more effective competitive inhibitor of CYP3A4-mediated clearance after a single-dose of NFV due to modest accumulation of metabolites such as AG1402 during NFV multiple dosing. These metabolites also bind CYP3A4 and potentially may displace IDV from the enzyme binding site, thereby decreasing the extent of inhibition by IDV. Alternatively, it is possible that a modest effect of IDV on the NFV pharmacokinetic was present but not identified in the current study due to the lack of concurrent NFV monotherapy data from the same subjects. An additional potential reason is that CYP2C19 may be at least as important as CYP3A4 as a route of elimination for NFV in the multiple-dose situation. It is likely that during multiple-dosing [i.e., after NFV autoinduction and modest accumulation of CYP3A4-inhibiting metabolite(s) has taken place], CYP3A4 becomes less important and CYP2C19 becomes more important as the mediator of NFV clearance compared to the single-dose situation. Consequently, since IDV is an inhibitor of CYP3A4, but not of CYP2C19, the inhibitory effect of IDV on NFV becomes diminished during multiple dosing.

The observed discordance between the single- and multiple-dose study results is not likely to be explained by differences in drug interaction phenomena between HIV-1-infected and uninfected individuals. Although modest differences in drug pharmacokinetics have occasionally been noted between HIV-1-infected and uninfected subjects, to our knowledge there have been no reports of pronounced interactions occurring in one group but not the other. Thus, the differences noted above between the single- and multiple-dose drug interaction studies for IDV plus NFV most likely reflect changes in metabolism occurring between single and multiple dosing with these medications. The findings of the present study highlight that single-dose drug interaction data may be used to guide initial dose selection for multiple-dose studies but that multiple-dose steady-state pharmacokinetic studies must be performed in order to provide the most accurate dosing recommendations for clinical use of antiretroviral combinations. Ideally, these dose-finding pharmacokinetic studies should be performed in HIV-1-negative volunteers in order to avoid the risk of suboptimal dosing of potent antiretroviral agents in HIV-1-infected patients.

The combination of IDV and NFV was generally well tolerated, with few toxicity-related discontinuations. No unexpected, drug-related adverse events occurred, and there were no dose-limiting toxicities with this regimen. Although the present study was based on available knowledge, this regimen would not be currently recommended for therapy without the addition of two NRTIs. It is interesting that a sustained virologic response was seen in 45% of the subjects (HIV-1 RNA level in plasma, <400 copies/ml) at week 72 (intent-to-treat) even though the initial regimen may not have been optimal. None of the subjects who withdrew from the study prior to week 72 had HIV-1 RNA levels of <400 copies/ml at the time of study discontinuation. Consistent with previous studies, none of the five subjects who experienced virologic failure had achieved an undetectable viral load while in the study, thus emphasizing the relationship between the viral load nadir and virologic success. The reasons for virologic failure with potent antiretroviral regimens include incomplete adherence, the presence of preexistent mutations conferring drug resistance, and individual differences in absorption or metabolism. In the present study, there were no mutations associated with IDV or NFV resistance in the baseline samples from subjects who later experienced virologic failure (data not shown). Additionally, there was no significant difference in the pharmacokinetic parameters of the subjects with sustained virologic suppression compared to those experiencing virologic failure. It is possible that the initial regimen used in the present study, a combination of two PIs without NRTIs, was not potent enough to suppress or maintain the suppression of HIV-1 RNA in plasma in some subjects, especially those with more advanced disease. Current treatment guidelines recommend antiretroviral regimens with a minimum of three active agents are optimal for the treatment of HIV-1 infection (U.S. Department of Health and Human Services [http://hivatis.org/trtgdlns.html]).

A large randomized treatment study using the combination of IDV and NFV with two NRTIs in PI and NNRTI naive subjects with advanced HIV-1 infection has recently been completed by the AIDS Clinical Trials Group (protocol 388). The results of the present study may provide additional insight into the clinical use of this combination.

In summary, the coadministration of IDV and NFV was generally well tolerated in subjects with moderately advanced HIV-1 infection. The combination of IDV at 1,200 mg at q12h and NFV at 1,250 mg q12h results in pharmacokinetic parameters for each drug that are comparable to those observed with IDV and NFV given alone or in combination with NRTIs.

	ACKNOWLEDGMENTS

 
This study was supported by Merck & Co., Inc., and by National Institutes of Health NCRR/GCRC grant M01 RR00056.

We thank the study participants and the research staff (N. Mantz, K. Nuffer, J. House, D. Davis, and S. Wright).

	FOOTNOTES

 
* Corresponding author. Mailing address: Division of Infectious Diseases, Falk Medical Bldg., Rm. 611, 3601 Fifth Ave., Pittsburgh, PA 15213. Phone: (412) 647-6710. Fax: (412) 647-5519. E-mail: riddler{at}msx.dept-med.pitt.edu.

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