JAIDS Journal of Acquired Immune Deficiency Syndromes:
Coadministration of Lopinavir/Ritonavir and Phenytoin Results in Two-Way Drug Interaction Through Cytochrome P-450 Induction
Lim, Michael L. PharmD*; Min, Sherene S. MD†; Eron, Joseph J. MD†; Bertz, Richard J. PhD‡; Robinson, Marjorie PharmD‡; Gaedigk, Andrea PhD§; Kashuba, Angela D. M. PharmD*
From *School of Pharmacy and †School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; ‡Abbott Laboratories, Clinical Pharmacokinetics and Antiviral Global Team, Abbott Park, IL; and §The Children’s Mercy Hospital and Clinics, Division of Pediatric Pharmacology and Experimental Therapeutics, Kansas City, MO.
Received November 7, 2003; accepted for publication April 22, 2004.
Research grant support provided by Abbott Laboratories, the UNC Center for AIDS Research (P30A150410), the UNC General Clinical Research Center (RR00046), and the UNC Clinical Research Nutrition Research Center (DK56350). At the time of study, Dr. Lim received fellowship support from GlaxoSmithKline; Dr. Min received support from NIH grant 5T32AI07001; Dr. Eron received support from NIH grant AI25868; and Dr. Kashuba received support from NIH grant AI54980.
This research was presented in part at the 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 10–14, 2003, and the American College of Clinical Pharmacy Spring Practice and Research Forum, Palm Springs, CA, April 27–30, 2003.
Drs. Lim, Min, Gaedigk, and Kashuba do not have conflicts of interest related to this research or manuscript. Drs. Bertz and Robinson are employed by Abbott Laboratories. Dr. Eron is an ad hoc consultant to Abbott Laboratories and receives support for conduct of clinical trials sponsored by Abbott Laboratories through the University of North Carolina.
Reprints: Angela D. M. Kashuba, University of North Carolina, School of Pharmacy, Kerr Hall, CB#7360, Chapel Hill, NC 27599 (e-mail: email@example.com).
Summary: Lopinavir/ritonavir (LPV/RTV) is a CYP3A4 inhibitor and substrate; it also may induce cytochrome P-450 (CYP) isozymes. Phenytoin (PHT) is a CYP3A4 inducer and CYP2C9/CYP2C19 substrate. This study quantified the pharmacokinetic (PK) drug interaction between LPV/RTV and PHT. Open-label, randomized, multiple-dose, PK study in healthy volunteers. Subjects in arm A (n = 12) received LPV/RTV 400/100 mg twice daily (BID) (days 1–10), followed by LPV/RTV 400/100 mg BID + PHT 300 mg once daily (QD) (days 11–22). Arm B (n = 12) received PHT 300 mg QD (days 1–11), followed by PHT 300 mg QD + LPV/RTV 400/100 mg BID (days 12–23). Plasma samples were collected on day 11 and day 22; PK parameters were compared by geometric mean ratio (GMR, day 22:day 11). P values <0.05 were considered significant. Following PHT addition, LPV area under the concentration-time curve (AUC0-12h) decreased from 70.9 ± 37.0 to 49.6 ± 25.1 μg·h/mL (GMR 0.67, P = 0.011) and C0h decreased from 6.0 ± 3.2 to 3.6 ± 2.3 μg/mL (GMR 0.54, P = 0.001). Following LPV/RTV addition, PHT AUC0-24h decreased from 191.0 ± 89.2 to 147.8 ± 104.5 μg·h/mL (GMR 0.69, P = 0.009) and C0h decreased from 7.0 ± 4.0 to 5.3 ± 4.1 μg/mL (GMR 0.66, P = 0.033). Concomitant LPV/RTV and PHT use results in a 2-way drug interaction. Phenytoin appears to increase LPV clearance via CYP3A4 induction, which is not offset by the presence of low-dose RTV. LPV/RTV may increase PHT clearance via CYP2C9 induction. Management should be individualized to each patient; dosage or medication adjustments may be necessary.
Antiretroviral drug concentrations are an important determinant of successful HIV therapy; several investigations have demonstrated a correlation between protease inhibitor (PI) plasma concentrations and clinical response. 1–4 One strategy used to optimize PI pharmacokinetics (PK) is to combine low doses of the PI ritonavir (RTV) with a second PI. Ritonavir is a potent inhibitor of cytochrome P-450 (CYP) 3A4, the primary enzyme responsible for the metabolism of most PIs. 5 The coformulation of lopinavir (LPV) and ritonavir (RTV) exploits this strategy to markedly enhance LPV plasma concentrations. Lopinavir administered alone produces low plasma concentrations, but with RTV coadministration, plasma concentrations are elevated and sustained throughout the dosing interval. 6,7 The LPV/RTV combination has demonstrated efficacy in both treatment-naive and experienced populations. 8–12
Because PIs often inhibit, induce, or are metabolized by the CYP enzyme system, management of drug-drug interactions in HIV patients is challenging. 13 Those who require concomitant use of anticonvulsants and PIs present a particularly difficult clinical dilemma. 14 Several anticonvulsants, including phenytoin (PHT), carbamazepine, and phenobarbital, are inducers of CYP isozymes and are also metabolized via this enzyme system. Thus, coadministration of CYP-inducing anticonvulsants can decrease PI concentrations, which may compromise antiretroviral efficacy and potentially lead to drug resistance. Conversely, use of PIs that inhibit or induce the CYP enzyme system may increase or decrease anticonvulsant concentrations. These concerns are substantiated by a case report describing antiretroviral failure when PIs and anticonvulsants were coadministered. 15 Similarly, both anticonvulsant toxicity and lack of efficacy have been described with PI coadministration. 16–20 Clinical data on drug–drug interactions between anticonvulsants and PIs are needed to minimize these hazards and guide clinical management.
The primary objective of this study was to determine the effects of PHT coadministration on the PK of LPV/RTV and to determine the effects of LPV/RTV on the PK of PHT. A secondary objective was to explore whether any correlation exists between genetic polymorphisms associated with altered activity of drug-metabolizing or transport enzymes and the PK of LPV/RTV and PHT.
Study subjects (n = 24) were male and female volunteers assessed at screening to be healthy by physical examination, medical history, laboratory evaluations, and 12-lead electrocardiogram. Inclusion criteria were as follows: weight of at least 70 kg, age between 18–45 years, and HIV seronegativity. Exclusion criteria were as follows: significant medical conditions or laboratory abnormalities (including hyperlipidemia); weight >50% above ideal body weight; current history of alcohol or drug abuse; inability to abstain from alcohol or grapefruit juice; current use of any CYP inhibitors or inducers; current use of CYP3A, CYP2D6, or CYP2B6 substrates with dose-dependent toxicity; current use of any complementary or alternative medications; and a history of allergy to any study medication. Sexually active women were required to have a negative pregnancy test and to use barrier contraception during the study. The University of North Carolina Institutional Review Board approved the study protocol, and all subjects provided written informed consent before any study procedures.
LPV/RTV (Kaletra; Abbott Laboratories, Abbott Park, IL) was administered orally at the usual clinical dose of 400/100 mg twice daily. PHT (Dilantin; Parke-Davis, Morris Plains, NJ) was administered orally each evening as a 300-mg dose. Subjects were instructed to take all medications with food and to take LPV/RTV and PHT simultaneously during coadministration periods. Medication adherence was evaluated by pill counts and diaries. During inpatient visits, standardized meals (average 828 kcal, 30% fat) were served immediately following administration of the PK dose and completed within 30 minutes. Blood samples for PK analysis were collected in 10-mL EDTA tubes (LPV/RTV) and 7-mL sodium heparin tubes (PHT).
This was an open-label, randomized, multiple-dose, parallel-arm, 2-period PK study. Following a screening visit and confirmation that all entry criteria were met, subjects were randomly assigned 1:1 to one of two arms.
Subjects in arm A (n = 12) self-administered LPV/RTV twice daily on an outpatient basis for 10 days. On day 10, subjects were admitted to the University of North Carolina General Clinical Research Center (GCRC) and the evening LPV/RTV dose was observed at 7 pm. On day 11, a predose blood sample was collected at 6:55 am, followed by the morning LPV/RTV dose at 7 am, immediately followed by a standardized meal. Additional blood samples were collected at 2, 4, 6, 8, 10, and 12 hours after dose administration. Lunch was permitted after the 4-hour sample. Following the 12-hour sample, subjects were discharged after an observed dose of LPV/RTV and PHT 300 mg. Subjects continued to take LPV/RTV and PHT as outpatients for days 12–21. On day 21, subjects were admitted to the GCRC and the evening LPV/RTV and PHT doses were observed at 7 pm. On day 22, a predose blood sample was collected at 6:55 am, followed by the morning LPV/RTV dose at 7:00 am, immediately followed by a standardized meal and additional blood sample collections as per the previous visit. Following the 12-hour sample, subjects in arm A completed the study and were discharged home.
Subjects in arm B (n = 12) self-administered PHT every evening on an outpatient basis for 10 days. On day 11, subjects were admitted to the GCRC. At 6:55 pm, a predose blood sample was collected, followed by the evening PHT dose at 7 pm and a standardized meal. Additional blood samples were collected at 2, 4, 6, 12, and 24 hours after dose administration. Breakfast and lunch were allowed after the 12-hour blood sample. Following the 24-hour sample, the evening PHT dose was administered with LPV/RTV 400/100 mg orally, and subjects were discharged. Subjects continued to take PHT each evening and LPV/RTV twice daily as outpatients for days 13–22. On day 22, subjects were admitted to the GCRC. At 6:55 pm, a predose blood sample was collected, followed by the evening PHT and LPV/RTV doses at 7 pm, immediately followed by a standardized meal and additional blood sample collections as per the previous visit. After the 24-hour sample, subjects in arm B completed the study and were discharged home.
Safety assessments at each PK visit included laboratory evaluations (complete blood count, chemistry panel, liver function tests, cholesterol, PHT trough concentration), physical examination, and adverse event assessment. Five days after beginning PHT, subjects returned for additional laboratory evaluations and adverse event assessment.
Following blood collection, plasma was separated by centrifugation at 2800 rpm for 15 minutes at 4°C and stored temporarily at the GCRC at −20°C. Frozen plasma samples were held in a −80°C freezer for longer-term storage prior to analysis.
Lopinavir and Ritonavir
LPV and RTV plasma concentrations were assayed using a validated LC/MS/MS method in compliance with good laboratory practices. Briefly, each 0.5-mL plasma sample was mixed, vortexed, and centrifuged with 0.5 mL 0.5 M sodium carbonate, 0.1 mL internal standard (A-86093.0), and 5 mL methyl-tert-butyl ether. The organic layer was transferred and evaporated to dryness under nitrogen and low heat. Dried residues were reconstituted in mobile phase, vortexed, centrifuged, and transferred to autosampler vials. Samples were run on a Waters Novapak C18 column with 60:40 acetonitrile/50 m M ammonium formate mobile phase. Calibration curves for LPV and RTV ranged from 5.0 ng/mL–10,000.0 ng/mL and from 1.0–1000.0 ng/mL, respectively. Mean standard curve correlation coefficients for 4 LPV and RTV runs were 0.9985 and 0.9992, respectively. Overall precision (%CV) for LPV and RTV was ≤4.254 and ≤2.120%, respectively. Accuracy (% recovery) ranged from 90.897–108.725% for LPV and from 101.908–106.000% for RTV.
PHT plasma concentrations were assayed using a validated LC/UV method in compliance with good laboratory practices. Briefly, each 0.5-mL plasma sample was mixed, vortexed, and centrifuged with 0.2 mL pentobarbital internal standard and 3 mL ethyl ether. The organic layer was transferred and evaporated to dryness under nitrogen and low heat. Samples were reconstituted in mobile phase and run on a Waters Novapak C-18 column with 65:35:4 water/methanol/tetra-hydrofuran mobile phase and UV detection at 230 n M. Calibration curves for PHT ranged from 0.050–25.0 μg/mL and mean standard curve correlation coefficient for 4 runs was 0.9977. Overall precision for PHT was ≤12.5%, and accuracy ranged from 99.606–98.17%.
Blood samples for genetic analyses were collected in an EDTA tube at screening and DNA extraction was performed using the QiaAMP blood DNA isolation kit (Qiagen, Valencia, CA). Genotyping using polymerase chain reaction restriction fragment length polymorphism (RFLP)-based procedures was used to detect allelic variants for CYP2C9 (*2–*6), CYP2C19 (*2–*8), CYP3A5 (*2–*7), CYP3A4 *1B, and MDR-1 1236 C>T (exon 12), 2677 G>T/A (exon 21), and 3435 C>T (exon 26). If no sequence variations were detected, allele assignment defaulted to *1 or wild type, respectively. For MDR-1, haplo-types were determined according to the presence of single-nucleotide polymorphisms, and genotype assignment was made based on nomenclature described by Chowbay et al 21 and Kim et al. 22
Data Analysis and Statistical Methods
Pharmacokinetic parameters were derived from plasma concentrations using noncompartmental methods (WinNonlin Pro 3.3, Pharsight, Mountain View, CA). The linear trapezoidal method was used to calculate area under the concentration-time curve (AUC0-τ). Geometric mean ratios were calculated to compare PK parameters between the 2 study periods (day 22/day 11). Statistical analyses for comparison of PK parameters during periods included multivariate analysis of variance and paired t test (SAS JMP 4.04 and Microsoft Excel 97 SR-2, Redmond, WA). A P value of <0.05 was considered significant. A priori sample size estimates indicated 9 evaluable subjects in arm A would provide 85% power to detect a 25% change in median LPV AUC0-12h, assuming a between-period SD of 0.22 μg·h/mL and type I error of 0.05. An estimated 5 evaluable subjects in arm B would provide 80% power to detect a 25% change in mean PHT C24h, based on expectations of a between-period SD of 1.75 μg/mL. 23 Unless otherwise stated, data are reported as mean ± 1 SD.
Twenty-four healthy volunteers enrolled in this study; 20 completed all study visits and were included in PK analysis (n = 12 for arm A, n = 8 for arm B). The majority of enrolled subjects were male (92%) and white (88%). Age, weight, and height were 25 ± 5.9 years, 86.6 ± 12.5 kg, and 180.7 ± 7.4 cm, respectively.
Results of PK analyses are summarized in Figures 1 and 2 and Table 1. For subjects in arm A, concentration-time plots for LPV and RTV administered alone (day 11) and with PHT (day 22) demonstrated lower LPV and RTV concentrations after the addition of PHT (Fig. 1). Lopinavir C0h decreased by 46% and LPV AUC0-12h decreased by 33% after PHT was added (Table 1). In arm B, PHT concentrations decreased following the addition of LPV/RTV (day 22), compared with when administered alone (day 11) (Fig. 2). PHT C0h decreased by 33% and PHT AUC0-24h decreased by 31% after LPV/RTV was added (Table 1). Additional PK parameters are summarized in Table 1.
Genotyping for CYP enzymes involved in the metabolism or disposition of study drugs was performed. Additionally, genotyping for MDR-1, which encodes for the P-glycoprotein drug transporter, was performed. Results are as follows:CYP2C9 *1/*1 (n = 10), *1/*2 (n = 8), *1/*3 (n = 6); CYP2C19 *1/*1 (n = 19), *1/*2 (n = 5); CYP3A4 *1/*1 (n = 21), *1/*1B (n = 2), *1B/*1B (n = 1); CYP3A5 *1/*3 (n = 9), *3/*3 (n = 15). For MDR-1, 7 subjects were *1/*1, 8 subjects had one *2, *3, *4, *5, or *6 allele, and 9 subjects had two *2, *3, *4, *5, or *6 alleles. 22
Five subjects in arm B with CYP2C9 *1/*2 or *1/*3 genotypes had higher PHT concentrations than the 3 subjects with 2 functional CYP2C9 *1 alleles. Two subjects with MDR-1 *1/*1 and *1/*5 or *6 (lacking the MDR-1 *2 allele) also demonstrated higher PHT concentrations than the 6 with the MDR-1 *2 allele, although both were genotyped as CYP2C9 *1/*3 and *1/*2, respectively. No significant correlation between genotype and magnitude of change in drug exposure was noted, although the study was not powered to detect differences.
Study medications were generally well tolerated and the majority of adverse events were mild and resolved spontaneously. Adverse events typically did not require discontinuation. Four subjects in arm B discontinued prematurely; one of these discontinued prior to LPV/RTV addition. Reasons for discontinuation were rash (n = 2), gastrointestinal intolerance (n = 1), and gastrointestinal intolerance with grade I liver function test elevations (n = 1). Subjects in arm A who received LPV/RTV alone for 10 days experienced elevations in fasting total cholesterol and triglycerides of 16.3 ± 22.8 (interquartile range [IQR]: −3.8, 25.5) mg/dL and 100.9 ± 120.5 (IQR: 36.8, 149.5) mg/dL, respectively, by day 11. For all subjects completing the study, fasting total cholesterol increased by 20.9 ± 29.1 (IQR: 7.0, 41.75) mg/dL and fasting triglycerides increased by 94.2 ± 85.3 (IQR: 16.8, 147.0) mg/dL over the entire study period.
An estimated 3–17% of HIV-infected patients experience seizures and those who experience new-onset seizures often have advanced HIV disease. 24–26 Over one-third of these seizures may be caused by AIDS-associated conditions such as cryptococcal meningitis, cerebral toxoplasmosis, central nervous system lymphoma, progressive multifocal leukoencephalopathy, and herpesvirus infections. 24–26 Although highly active antiretroviral therapy (HAART) has reduced the incidence of these conditions, patients with epilepsy may also be HIV infected. Additionally, anticonvulsants are commonly used for alternate conditions including bipolar disease, neuropathic pain, and migraine headaches. 27–29 Thus, anticonvulsants may be indicated across a broad spectrum of HIV-infected patients. As PHT is the most frequently prescribed anticonvulsant in HIV-infected patients, it is critical to understand its potential for drug interactions with antiretrovirals. 24,25
This study demonstrated a significant 2-way drug interaction between LPV/RTV and PHT. Concentrations of LPV and RTV were decreased by the addition of PHT and concentrations of PHT were decreased by the addition of LPV/RTV. Neither CYP3A, 2C9/19, nor MDR-1 genotype appeared to be predictive of the interaction, although the study was not adequately powered for these comparisons.
Because the primary LPV/RTV metabolic pathway is through the CYP3A subfamily, induction of CYP3A by PHT would account for these decreased LPV/RTV concentrations. Induction of CYP3A by PHT, leading to decreased concentrations of CYP3A substrates, has been described previously; however, the inclusion of low-dose RTV, a potent CYP3A inhibitor, did not alleviate this effect. It is noteworthy that RTV concentrations were also reduced in the presence of PHT, which may partially account for the lower LPV exposures. Other potential contributors to LPV/RTV concentrations include ABC transporters such as the efflux transport protein, P-glycoprotein. Recent investigations suggest a potential correlation between MDR-1 genotype and pharmacokinetics of PIs, although a complete understanding is still evolving. 30,31 No correlation was noted in the present study, and PHT does not appear to induce P-glycoprotein in vitro, although its effects on other drug transport proteins that may potentially affect LPV/RTV are currently unknown. 32,33 Thus, CYP3A induction by PHT is the likely mechanism for this interaction.
A PHT dose of 300 mg QD is commonly prescribed in clinical practice and was also used in this study. Despite lowered PHT concentrations in the presence of LPV/RTV, a 46% decrease in LPV C0h was still observed. Although this study could not determine whether higher doses of PHT would result in further decreases in LPV/RTV concentrations, the findings underscore the vulnerability of PIs to induction drug interactions, especially in light of the similar magnitudes of decreased LPV/RTV concentrations described with coadministration of the antiretrovirals efavirenz and amprenavir. 10,34,35
PHT concentrations decreased following addition of LPV/RTV. PHT is metabolized predominantly by CYP2C9 and partially by CYP2C19. At the concentrations of PHT achieved in this study, CYP2C9 is expected to be the dominant pathway. 36 This suggests that LPV/RTV is an inducer of CYP2C9. To our knowledge, this is the first clinical study to describe CYP2C9 induction by LPV/RTV and may have clinical relevance for patients requiring therapy with other CYP2C9 substrates. This in vivo finding is in contrast to in vitro data suggesting that LPV/RTV is a very weak inhibitor of CYP2C9 (Ki = 13.7–23.0 μM); however, these experiments were not designed to evaluate induction. 5 Because PHT metabolism and elimination are complex, appropriate in vitro experiments to confirm induction of CYP2C9 by LPV/RTV, or clinical investigations utilizing appropriate CYP2C9 phenotyping biomarkers, represent potentially interesting avenues for further investigation.
A contributory role of P-glycoprotein, for which PHT is a substrate, cannot be ruled out. 37 However, the question of whether LPV/RTV appreciably induces P-glycoprotein is controversial and based solely on in vitro studies. 38–40 Although the plausibility of P-glycoprotein induction altering concentrations of a substrate such as PHT is uncertain, the ability of LPV/RTV to significantly decrease CYP substrates has been established. 10,34,35 In our study, PHT concentrations correlated more closely with CYP2C9 genotype than MDR-1 genotype, consistent with other observations. 37 Thus, induction of CYP2C9 by LPV/RTV appears to be a more likely explanation. Case reports of decreased warfarin activity, a CYP2C9 substrate that is not transported by P-glycoprotein, when coad-ministered with RTV, support this conclusion. 41,42
Although significant two-way induction was observed in healthy volunteers, several management options may be considered in clinical practice. However, because the present study was not designed to evaluate alternate dosing strategies, until further data are available, the following LPV/RTV dosing strategies should be considered only with very close clinical follow-up and concurrent therapeutic drug monitoring, if available. Increasing LPV/RTV to 533/133 mg BID is recommended when LPV/RTV is coadministered with the inducer efavirenz and thus could be considered during coadministration with PHT. 34 Increasing RTV dosage to a total LPV/RTV dose of 400/200 mg BID is another option, although the additional RTV may make this regimen less tolerable and convenient.
Very few data exist on drug interactions between PHT and other antiretrovirals. A previous study of PHT and the PI nelfinavir (NFV) reported that NFV concentrations were not significantly altered by the addition of PHT, although PHT concentrations were decreased by a similar magnitude of ~30%. 23 However, the active NFV metabolite, M8, was reduced by PHT, which may discourage against switching to NFV to manage this interaction. 23 All other PIs (eg, indinavir, saquinavir, amprenavir, atazanavir) are metabolized by CYP3A and are likely to also be susceptible to interactions with PHT.
PHT is a first-line treatment of partial seizures, and continued coadministration with LPV/RTV may be possible for some patients, as described above. 43 However, decreases in PHT concentrations may be clinically significant or associated with poor seizure control. In these cases, increases in PHT dosage or changes in anticonvulsant regimens may be required. Changes in PHT dosages should be done with caution, as disproportionate increases in PHT concentrations may result from small increases in dose, owing to PHT’s nonlinear PK. PHT dose adjustments should use small increases (30–50 mg), with steady-state monitoring of PHT concentrations and clinical assessment for drug toxicity at least weekly. Continued LPV/RTV monitoring is also prudent, as it is unknown whether achieving higher PHT concentrations will further decrease LPV/RTV concentrations. Alternate anticonvulsants may also be considered as substitutes or adjuncts to PHT. Caution is advised for carbamazepine, oxcarbazepine, and phenobarbital, as CYP induction has also been demonstrated with these agents. Anticonvulsants with lower propensity for CYP induction–mediated drug interactions include gabapentin, valproic acid, and levetiracetam. Valproic acid may stimulate in vitro replication of HIV, although the clinical relevance in patients receiving suppressive HAART is unknown. 14
This clinical study demonstrated a significant 2-way PK interaction between LPV/RTV and PHT. The decrease in LPV/RTV concentrations may be clinically significant, particularly in patients with decreased antiretroviral drug susceptibility or poor adherence. Furthermore, due to decreased PHT exposure when combined with LPV/RTV, close monitoring of PHT concentration is recommended. Management of these drug interactions may require changes in dosage or alterations of antiretroviral or anticonvulsant regimens. These changes must be individualized to each patient and must consider both PK data and clinical considerations to optimize use of both PIs and anticonvulsants.
The authors gratefully acknowledge Paul Stewart, Sharon Leu, and Jessica Lim for statistical assistance; Prema Menezes and Luigi Troiani for clinical assistance; Chris Zurich of Abbott Laboratories for assistance with grants and contracts; PPD Development and Prevalere Life Sciences for analytical support; the research volunteers, and the nurses and staff of the UNC General Clinical Research Center.
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