ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects.

BACKGROUND: Dolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF). METHODS: ING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy-naive, HIV-1-infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16. RESULTS: Thirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non-drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4-23 ng/mL) at week 2 and 13 ng/mL (4-18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were -3.42 and -3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16. CONCLUSIONS: The DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma. Clinical Trials Registration. NCT01499199.

Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans.

The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [(14)C]dolutegravir at a dose of 20 mg (80 µCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (t1/2) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.

Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers.

OBJECTIVES: To evaluate the effect of pH-altering agents on S/GSK1349572 exposure in healthy subjects. METHODS: S/GSK1349572 is an unboosted, once-daily, next-generation HIV integrase inhibitor. In the first study, 16 subjects received four single-dose treatments: (i) S/GSK1349572 50 mg; (ii) S/GSK1349572 50 mg with a multivitamin (MVI; One A Day Maximum); (iii) S/GSK1349572 50 mg with a liquid antacid (Maalox Advanced Maximum Strength); and (iv) S/GSK1349572 50 mg 2 h before an antacid. In the second study, 12 subjects received a single dose of S/GSK1349572 alone and on day 5 of omeprazole. RESULTS: All treatments were well tolerated. MVI co-administration modestly decreased S/GSK1349572 AUC by 33%. Concurrent antacid co-administration reduced S/GSK1349572 AUC by 74% and staggered antacid dosing significantly diminished this interaction, with a reduction in S/GSK1349572 AUC of 26%. Omeprazole did not significantly affect S/GSK1349572 exposure. CONCLUSIONS: S/GSK1349572 can be taken with proton pump inhibitors and MVIs without dose adjustment but should be administered 2 h before or 6 h after antacids.

Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development.

This white paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of ventricular arrhythmias in early clinical pharmacology trials and their potential consequences for later clinical drug development. Ventricular arrhythmias are infrequent but potentially important medical events whose occurrence in early clinical pharmacology trials can dramatically increase safety concerns. Given the increasing concern with all potential safety signals and the resultant more extensive electrocardiographic monitoring of subjects participating in early phase trials, an important question must be addressed: Are relatively more frequent observations of ventricular arrhythmias related simply to more extensive monitoring, or are they genuinely related to the drug under development? The discussions in this paper provide current thinking and suggestions for addressing this question.

Steady-state pharmacokinetics of abacavir in plasma and intracellular carbovir triphosphate following administration of abacavir at 600 milligrams once daily and 300 milligrams twice daily in human immunodeficiency virus-infected subjects.

Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days -1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC(0-24)) and comparable CBV-TP concentrations at the end of the dosing interval (C(tau)). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (C(max)) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC(0-24) and 99% higher CBV-TP C(max) than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC(0-24) and 81% higher weight-adjusted CBV-TP AUC(0-24) than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C(tau) values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.

Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization.

STUDY OBJECTIVE: To assess the effect of a supratherapeutic dose of the integrase inhibitor dolutegravir on the QT and corrected QT (QTc) interval. DESIGN: Randomized, partial-blind, placebo-controlled, single-dose, 3-period, balanced crossover study. SETTING: Clinical research unit. SUBJECTS: Forty-two healthy subjects were randomized; of these subjects, 38 completed the study, three withdrew early because of protocol violations, and one was lost to follow-up. INTERVENTION: Subjects were randomized to receive three single doses of the following treatments: dolutegravir 250-mg suspension, moxifloxacin 400-mg tablet, and placebo suspension; each treatment was separated by a 14-day washout period. Treatment with the dolutegravir and placebo suspension was blinded, whereas treatment with moxifloxacin was open label. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetic exposure at a supratherapeutic dose of dolutegravir 250 mg was 2-4 times higher than the pharmacokinetic exposure at clinically relevant dosages (50 mg once or twice/day). The upper limit of the 90% confidence interval (CI) for the placebo-adjusted mean change from baseline of the QTc interval (ΔΔQTcF) using Fridericia's formula was less than 10 msec at all time points. The sensitivity of the study to detect modest increases in QT interval was established with moxifloxacin, a positive control for QT-interval prolongation. The maximum ΔΔQTcF values for dolutegravir and moxifloxacin were observed at 4 hours: 1.99 msec (90% CI -0.55-4.53 msec) and 9.58 msec (90% CI 7.05-12.11 msec), respectively. CONCLUSION: This pharmacokinetic-pharmacodynamic model demonstrates no relationship between dolutegravir plasma concentration and ΔΔQTcF. Furthermore, a supratherapeutic dose of dolutegravir was generally well tolerated without any serious or severe adverse events. As such, dolutegravir does not affect cardiac repolarization.

The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants.

S/GSK1349572 is an unboosted, once-daily integrase inhibitor with a novel resistance profile. As standard of care for patients infected with HIV is combination therapy, the potential interaction between S/GSK1349572 and ritonavir-boosted protease inhibitors was evaluated. In an open-label, repeat-dose, 2-period, 2-sequence crossover study in healthy participants, S/GSK1349572 was administered at 30 mg once daily for 5 days, followed by randomization to lopinavir/ritonavir 400/100 mg twice daily or darunavir/ritonavir 600/100 mg twice daily coadministered with S/GSK1349572 30 mg once daily for 14 days. There was no washout between periods. Serial pharmacokinetic (PK) samples and safety assessments were obtained throughout the study. Thirty of 31 participants completed the study (15 participants per group). Treatment comparisons of steady-state S/GSK1349572 PK parameters demonstrated that coadministration of lopinavir/ritonavir had no significant effect on steady-state PK of S/GSK1349572. Coadministration of darunavir/ritonavir resulted in a nonclinically significant reduction in steady-state plasma S/GSK1349572 exposures. Plasma S/GSK1349572 AUC((0-τ)), C(max), and C(τ) decreased by 22%, 11%, and 38%, respectively, on average. S/GSK1349572 was well tolerated with no serious adverse events (AEs) or withdrawals due to drug-related AEs. The most frequent drug-related AEs were diarrhea, dizziness, and headache. No dosage adjustment for S/GSK1349572 is required when used with lopinavir/ritonavir or darunavir/ritonavir.

Lack of interaction between the HIV integrase inhibitor S/GSK1349572 and tenofovir in healthy subjects.

BACKGROUND: The potential for a drug interaction between S/GSK1349572 and tenofovir disoproxil fumarate (TDF) was evaluated in an open-label, repeat dose, 3-period, drug-drug interaction study in healthy subjects. METHODS: S/GSK1349572 was administered at 50 mg once daily for 5 days (period 1) followed by a 6-day washout period. TDF 300 mg once daily was then administered for 7 days (period 2). The combination of S/GSK1349572 and TDF was then coadministered for 5 days (period 3). Pharmacokinetic parameters were determined and compared between periods. RESULTS: Fifteen subjects completed all periods and follow-up. S/GSK1349572 and TDF were generally well tolerated with few adverse events reported. No clinically significant trends in post-dose laboratory abnormalities, vital signs, or electrocardiogram values were noted. Pharmacokinetic parameters of S/GSK1349572 and tenofovir during combination therapy were similar to those when given alone, demonstrating no significant drug interaction. S/GSK1349572 geometric least squares mean ratios (90% confidence interval) for AUC(0-τ), Cmax, and Cτ were 1.01 (0.908, 1.11), 0.969 (0.867, 1.08), and 0.920 (0.816, 1.04), respectively. Tenofovir geometric least squares mean ratios (90% confidence interval) for AUC(0-τ), Cmax, and Cτ were 1.12 (1.01, 1.24), 1.09 (0.974, 1.23), and 1.19 (1.04, 1.35), respectively. CONCLUSION: S/GSK1349572 and TDF can be coadministered without dose adjustment.

Pharmacokinetic interaction between fosamprenavir-ritonavir and rifabutin in healthy subjects.

Rifabutin (RFB) is administered for treatment of tuberculosis and Mycobacterium avium complex infection, including use for patients coinfected with human immunodeficiency virus (HIV). Increased systemic exposure to RFB and its equipotent active metabolite, 25-O-desacetyl-RFB (dAc-RFB), has been reported during concomitant administration of CYP3A4 inhibitors, including ritonavir (RTV), lopinavir, and amprenavir (APV); therefore, a reduction in the RFB dosage is recommended when it is coadministered with these protease inhibitors. Fosamprenavir (FPV), the phosphate ester prodrug of the HIV type 1 protease inhibitor APV, is administered either with or without RTV. A randomized, open-label, two-period, two-sequence, balanced, crossover drug interaction study was conducted with 22 healthy adult subjects to compare steady-state plasma RFB pharmacokinetic parameters during concomitant administration of FPV-RTV (700/100 mg twice a day [BID]) with a 75%-reduced RFB dose (150 mg every other day [QOD]) to the standard RFB regimen (300 mg once per day [QD]) by geometric least-squares mean ratios. Relative to results with RFB (300 mg QD), coadministration of dose-adjusted RFB with FPV-RTV resulted in an unchanged RFB area under the concentration-time curve for 0 to 48 h (AUC(0-48)) and a 14% decrease in the maximum concentration of drug in plasma (C(max)), whereas the AUC(0-48) and C(max) of dAc-RFB were increased by 11- and 6-fold, respectively, resulting in a 64% increase in the total antimycobacterial AUC(0-48). Relative to historical controls, the plasma APV AUC from 0 h to the end of the dosing interval (AUC(0-tau)) and C(max) were increased approximately 35%, and the concentration at the end of the dosing interval at steady state was unchanged following coadministration of RFB with FPV-RTV. The safety profile of the combination of RFB and FPV-RTV was consistent with previously described events with RFB or FPV-RTV alone. Based on the results of this study, a reduction in the RFB dose by > or =75% (to 150 mg QOD or three times per week) is recommended when it is coadministered with FPV-RTV (700/100 mg BID).

Effect of omeprazole on the plasma concentrations of indinavir when administered alone and in combination with ritonavir.

PURPOSE: The effects of omeprazole on indinavir when administered alone or in combination with ritonavir were evaluated. METHODS: Fourteen men and women age 18-55 years not infected with human immunodeficiency virus who met study qualifications were randomized to receive placebo, 20 mg of omeprazole, or 40 mg of omeprazole daily. After seven days, the single-dose pharmacokinetic profile of an 800-mg dose of indinavir alone or in combination with 200 mg of ritonavir was evaluated. Study participants received each of four study regimens in one of four randomly assigned orders. Blood samples were collected, and plasma indinavir and ritonavir concentrations were analyzed using high-performance liquid chromatography. RESULTS: The coadministration of 20 or 40 mg of omeprazole with indinavir significantly reduced the mean indinavir area under the concentration-versus-time curve (AUC) from 30.0 mg x hr/L (95% confidence interval [CI], 21.9-41.1 mg x hr/L) to 19.7 mg x hr/L (95% CI, 14.6-26.8 mg x hr/L) or 16.0 mg x hr/L (95% CI, 11.8-21.7 mg x hr/L), respectively (p < 0.002). The addition of 200 mg of ritonavir to 800 mg of indinavir in combination with 40 mg of omeprazole significantly increased the mean indinavir AUC from 30.0 mg x hr/L (95% CI, 21.9-41.1 mg x hr/L) to 46.6 mg x hr/L (95% CI, 34.0-63.8 mg x hr/L), but it did not significantly affect mean omeprazole concentrations (p < or = 0.02). CONCLUSION: The AUC of indinavir was substantially decreased in healthy volunteers who received omeprazole 20 or 40 mg daily for seven days before the administration of a single 800-mg dose of indinavir. Concomitant administration of ritonavir 200 mg with indinavir in participants receiving omeprazole led to a significant increase in the AUC of indinavir.

Safety and pharmacokinetics of GSK364735, a human immunodeficiency virus type 1 integrase inhibitor, following single and repeated administration in healthy adult subjects.

GSK364735 is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor with potent in vitro antiviral activity. This study was a double-blind, randomized, placebo-controlled, dose escalation, phase I study to assess single- and repeated-dose safety, tolerability, pharmacokinetics (PK), and food effect of GSK364735 in healthy subjects. In part A, three alternating cohorts of 10 subjects (8 receiving the active drug and 2 receiving a placebo) received single doses of 50 to 400 mg while fasting or 200 mg and 400 mg coadministered with food. In part B, five cohorts received repeated doses of 100 to 600 mg daily coadministered with food for 8 days. Safety was assessed throughout the study. Serial blood samples were analyzed for GSK364735 plasma concentrations using a validated high-performance liquid chromatography-tandem mass spectrometry assay. PK parameters were estimated using noncompartmental methods. Seventy-nine (30 in part A and 49 in part B) subjects were enrolled and received GSK364735 or placebo. GSK364735 was readily absorbed following oral dose administration, with the maximum concentration achieved between 0.75 to 5.0 h postdose. GSK364735 exposure increased less than dose proportionally, demonstrated wide variability, and appeared to reach a plateau at 100- to 200-mg doses. Food increased GSK364735 exposure by 28 to 91%. GSK364735 was safe and well tolerated after single- and repeated-dose administration. No serious or severe adverse events (AEs) or AEs leading to withdrawal and few drug-related AEs were reported. Despite solubility-limited absorption, GSK364735 exceeded therapeutic trough concentrations for the majority of doses studied. The PK and safety profile supported the continued investigation of GSK364735 in HIV-infected subjects.

Pharmacokinetic and safety evaluation of high-dose combinations of fosamprenavir and ritonavir.

High-dose combinations of fosamprenavir (FPV) and ritonavir (RTV) were evaluated in healthy adult subjects in order to select doses for further study in multiple protease inhibitor (PI)-experienced patients infected with human immunodeficiency virus type 1. Two high-dose regimens, FPV 1,400 mg twice a day (BID) plus RTV 100 mg BID and FPV 1,400 mg BID plus RTV 200 mg BID, were planned to be compared to the approved regimen, FPV 700 mg BID plus RTV 100 mg BID, in a randomized three-period crossover study. Forty-two healthy adult subjects were enrolled, and 39 subjects completed period 1. Due to marked hepatic transaminase elevations, predominantly with FPV 1,400 mg BID plus RTV 200 mg BID, the study was terminated prematurely. For FPV 1,400 mg BID plus RTV 100 mg BID, the values for plasma amprenavir (APV) area under the concentration-time profile over the dosing interval (tau) at steady state [AUC(0-tau)], maximum concentration of drug in plasma (C(max)), and plasma concentration at the end of tau at steady state (C(tau)) were 54, 81, and 26% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) were 49% higher, 71% higher, and 11% lower, respectively, than those for FPV 700 mg BID plus RTV 100 mg BID. For FPV 1,400 mg BID plus RTV 200 mg BID, the values for plasma APV AUC(0-tau), C(max), and C(tau) were 26, 48, and 32% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) increased 4.15-fold, 4.17-fold, and 3.99-fold, respectively, compared to those for FPV 700 mg BID plus RTV 100 mg BID. FPV 1,400 mg BID plus RTV 200 mg BID is not recommended due to an increased rate of marked hepatic transaminase elevations and lack of pharmacokinetic advantage. FPV 1,400 mg BID plus RTV 100 mg BID is currently under clinical evaluation in multiple PI-experienced patients.

Coadministration of esomeprazole with fosamprenavir has no impact on steady-state plasma amprenavir pharmacokinetics.

OBJECTIVES: To evaluate the drug interaction between fosamprenavir (FPV) and esomeprazole (ESO) after repeated doses in healthy adults. METHODS: Subjects received ESO 20 mg once daily (qd) for 7 days followed by either ESO 20 mg qd + FPV 1400 mg twice daily (bid) or ESO 20 mg qd + FPV 700 mg bid + ritonavir (RTV) 100 mg bid for 14 days in arms 1 and 2, respectively. After a 21- to 28-day washout, subjects received either FPV 1400 mg bid for 14 days (arm 1) or FPV 700 mg bid + RTV 100 mg bid for 14 days (arm 2). Pharmacokinetic sampling was conducted on the last day of each treatment. RESULTS: Simultaneous coadministration of ESO 20 mg qd with either FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid had no effect on steady-state amprenavir pharmacokinetics. The only effect on plasma ESO exposure was a 55% increase in area under the plasma concentration-time curve during a dosing interval, tau[AUC0-tau], after coadministration of ESO 20 mg qd with FPV 1400 mg bid. CONCLUSIONS: FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid may be coadministered simultaneously with ESO without dose adjustment. However, the impact of staggered administration of proton pump inhibitors (PPI) on plasma amprenavir exposure is unknown at present.

Interaction between fosamprenavir, with and without ritonavir, and nevirapine in human immunodeficiency virus-infected subjects.

Fosamprenavir (FPV) with and without ritonavir (RTV) was added to the antiretroviral regimens of human immunodeficiency virus-infected subjects receiving nevirapine (NVP) to evaluate this drug interaction. Significant reductions in plasma amprenavir exposure (25 to 35%) were observed following coadministration of 1,400 mg of FPV twice a day (BID) and 200 mg of NVP BID. A regimen of 700 mg of FPV BID plus 100 mg of RTV BID may be coadministered with NVP without dose adjustment.

Protease inhibitor and nonnucleoside reverse transcriptase inhibitor concentrations in the genital tract of HIV-1-infected women.

The pharmacokinetics of antiretrovirals (ARVs) in the female genital tract (FGT) are likely to influence vertical and sexual transmission of HIV, the development of viral resistance, and post-exposure prophylaxis regimens. This study is the first to compare ARV concentrations in direct aspirates of cervicovaginal fluid (CVF) and blood plasma (BP). This unique method provides direct assessment of concentrations without the confounding of cervicovaginal lavage dilution. Of 8 ARVs, CVF concentrations ranged from <10% to >100% of BP concentrations. These large differences in CVF penetration suggest that further research into ARV pharmacokinetics and drug efficacy in the FGT is necessary.

Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction.

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 microg.h/mL (GMR 0.67, P = 0.011) and C0h decreased from 6.0 +/- 3.2 to 3.6 +/- 2.3 microg/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 microg.h/mL (GMR 0.69, P = 0.009) and C0h decreased from 7.0+/-4.0 to 5.3+/-4.1 microg/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.