Abstract
Once-daily (QD) fosamprenavir (FPV) at 1,400 mg boosted with low-dose ritonavir (RTV) at 200 mg is effective when it is used in combination regimens for the initial treatment of human immunodeficiency virus infection. Whether a lower RTV boosting dose (i.e., 100 mg QD) could ensure sufficient amprenavir (APV) concentrations with improved safety/tolerability is unknown. This randomized, two 14-day-period, crossover pharmacokinetic study compared the steady-state plasma APV concentrations, safety, and tolerability of FPV at 1,400 mg QD boosted with either 100 mg or 200 mg of RTV QD in 36 healthy volunteers. Geometric least-square (GLS) mean ratios and the associated 90% confidence intervals (CIs) were estimated for plasma APV maximum plasma concentrations (Cmax), the area under the plasma concentration-time curve over the dosing period (AUC0-τ), and trough concentrations (Cτ) during each dosing period. Equivalence between regimens (90% CIs of GLS mean ratios, 0.80 to 1.25) was observed for the plasma APV AUC0-τ (GLS mean ratio, 0.90 [90% CI, 0.84 to 0.96]) and Cmax (0.97 [90% CI, 0.91 to 1.04]). The APV Cτ was 38% lower with RTV at 100 mg QD than with RTV at 200 mg QD (GLS mean ratio, 0.62 [90% CI, 0.55 to 0.69]) but remained sixfold higher than the protein-corrected 50% inhibitory concentration for wild-type virus, with the lowest APV Cτ observed during the 100-mg QD period being nearly threefold higher. The GLS mean APV Cτ was 2.5 times higher than the historical Cτ for unboosted FPV at 1,400 mg twice daily. Fewer clinical adverse drug events and smaller increases in triglyceride levels were observed with the RTV 100-mg QD regimen. Clinical trials evaluating the efficacy and safety of FPV at 1,400 mg QD boosted by RTV at 100 mg QD are now under way with antiretroviral therapy-naïve patients.
The discovery and widespread clinical use of low-dose ritonavir (RTV) as a pharmacokinetic enhancer (“booster”) of other human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitors (PIs) in antiretroviral combination treatment regimens have significantly advanced the medical management of HIV-infected patients (2, 5, 14). RTV is a potent inhibitor of cytochrome P450 3A4 (CYP3A4), the enzyme responsible for HIV-1 PI metabolism. Low-dose RTV inhibits the first-pass metabolism of HIV-1 PIs, which can result in either the increased absorption of the HIV-1 PI or a reduction in its hepatic metabolism, or both. Ultimately, this leads to more prolonged plasma half-lives and higher plasma concentrations of the RTV-boosted PI, which can allow lower total daily pill burdens and less frequent daily administration, factors shown to potentially enhance patient adherence to antiretroviral medication regimens (16).
Fosamprenavir (FPV), the prodrug of the HIV-1 PI amprenavir (APV), administered unboosted or boosted with RTV at 200 mg once daily (QD) or 100 mg twice daily (BID), has proved valuable in the treatment of antiretroviral therapy-naïve, HIV-infected patients receiving an abacavir-lamivudine nucleoside backbone (6,10), as has RTV-boosted FPV with this same backbone in the treatment of antiretroviral therapy-experienced patients (E. DeJesus, A. Lamarca, M. Sension, C. Beltran, and P. Yeni on behalf of the CONTEXT Study Team, 10th Conf. Retrovir. Opportunistic Infect., abstr. 178, 2003). FPV is generally well tolerated and confers little or no cross-resistance. In antiretroviral therapy-naïve patients, 48 weeks of treatment with FPV at 1,400 mg-RTV at 200 mg QD in combination with abacavir at 300 mg-lamivudine at 150 mg BID (n = 322) produced a clinical response similar to that of nelfinavir at 1,250 mg BID plus abacavir-lamivudine (n = 327) (58% versus 55% for patients with with HIV-1 RNA loads of <50 copies/ml; by intent-to-treat analysis, rebound/discontinuation equals clinical failure) (6).
Studies of ascending RTV boosting doses have shown an increase in adverse events and lipids when RTV doses greater than 200 mg daily are administered (2). Even boosting of PIs with RTV at 200 mg QD has been associated with RTV-related gastrointestinal adverse events and lipid elevations (2). Among study subjects who received FPV once daily in combination with 200 mg of RTV (6), the combination was generally well tolerated, although higher incidences of gastrointestinal adverse events were reported compared to the incidences among study subjects who received FPV without RTV (10). In addition, grade 3 or 4 hypertriglyceridemia (triglyceride levels, >750 mg/dl) was observed in roughly 6% of patients receiving FPV at 1,400 mg-RTV at 200 mg QD but by none of the patients receiving FPV at 1,400 mg BID without RTV.
To date, RTV boosting doses less than 200 mg/day have not been evaluated in combination with FPV. Finding the lowest possible RTV dose that can provide sufficient plasma APV drug exposures with few adverse events would have important treatment implications. Kurowski (M. Kurowski, 1st IAS Conf. HIV Pathogenesis Treatment, abstr. 351, 2001) conducted a crossover study with 32 healthy volunteers to evaluate the effects of different RTV boosting doses on the pharmacokinetics of APV. That investigator found no differences in the area under the plasma APV-versus-time curve (AUC) or the minimum APV concentration (Cmin) after a regimen of APV at 600 mg BID with RTV at either 50 or 100 mg BID or a regimen of APV at 1,200 mg QD with RTV at 100 or 200 mg QD. This suggests that a total daily RTV dose of 100 mg may be sufficient to adequately boost FPV; however, the use of a small sample size led to wide confidence intervals for the treatment comparisons. In the present study with healthy subjects, we evaluated the plasma APV pharmacokinetics and the tolerability of APV following administration of FPV at 1,400 mg-RTV at 100 mg QD versus those of FPV at 1,400 mg-RTV at 200 mg QD (the RTV dose approved by the Food and Drug Administration).
(The results of this study were presented in part in at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 30 October to 2 November 2004 [P. Ruane, A. Luber, M. B. Wire, Y. Lou, M. J. Shelton, C. T. Lancaster, and K. A. Pappa, Abstr. 44th intersci Conf. Antimicrob. Agents Chemother., poster A-449]).
MATERIALS AND METHODS
Study population and design.
This was a phase I, open-label, two-period, balanced-crossover, steady-state pharmacokinetic study conducted with approximately 40 healthy adult subjects at one study center (PPD Development, Austin, TX). Male and female subjects were eligible if they were 18 to 55 years of age and in good health, based on medical history, physical examination findings, and laboratory testing. Subjects were excluded if they were pregnant or lactating or had any of the following conditions: a history of or current clinically significant medical condition; a preexisting condition that interfered with normal gastrointestinal anatomy or motility; hepatic and/or renal function that could interfere with the absorption, metabolism, or excretion of a study drug; or positivity for HIV or hepatitis B virus surface antigen or hepatitis C virus antibody at screening. The subjects could not use prescription or nonprescription drugs that negatively interact with the study medications under investigation. The subjects were excluded for alcohol or illicit drug use that the investigator believed would contraindicate participation in the trial.
The protocol, the subject informed consent form, and the investigator's brochure were reviewed and approved by the study research consultant's institutional review board review committee prior to study initiation. All study subjects provided written informed consent to participate.
Subjects underwent screening assessments within 30 days of dosing to determine their eligibility. If they were enrolled, they were randomly assigned to one of two RTV dosing sequences. In sequence A, the subjects received FPV at 1,400 mg QD plus RTV at 100 mg QD for 14 days, followed by a 21- to 28-day washout, during which they received no study drug, and then 14 days of FPV at 1,400 mg QD plus RTV at 200 mg QD. In sequence B, the subjects received FPV at 1,400 mg QD plus RTV at 200 mg QD initially for 14 days, followed by a 21- to 28-day washout and then 14 days of FPV at 1,400 mg QD plus RTV at 100 mg QD. The subjects were confined to the study unit during each period, with all study drug doses being administered and ingestion being observed by study site personnel. The subjects were allowed to go home during the washout period. Twenty-four-hour pharmacokinetic sampling was performed on day 14 of each RTV dosing period. A follow-up visit for safety assessment was conducted 21 to 28 days after the discontinuation of the study drugs.
FPV was supplied as 700-mg tablets of Lexiva (GlaxoSmithKline, Research Triangle Park, NC) for oral administration (each tablet contained approximately 600 mg of APV molar equivalents). RTV was supplied as 100-mg soft gelatin capsules of Norvir (Abbott Laboratories, North Chicago, IL). All subjects were required to fast 10 h before study drug administration on days 11, 12, 13, and 14 of each study period. Study drug was administered with 240 ml of water on an empty stomach, and the subjects remained fasted for an additional 4 h after dosing on day 14 of both study periods.
Pharmacokinetic assessments and methods.
Plasma samples for APV concentration determination were obtained predosing on the mornings of days 11, 12, and 13. The pharmacokinetics of APV in plasma were assessed over 24 h following FPV-RTV administration on day 14 of each dosing period. Blood samples were obtained at −0.05 h (predosing) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after drug administration. Blood was collected in a sodium citrate-containing tube. Following collection, the sample was gently inverted 8 to 10 times to mix the anticoagulant with the whole blood and was then stored on ice or in a refrigerator prior to plasma extraction. Plasma was separated by refrigerated centrifugation and was stored at −20°C until analysis.
Plasma APV and FPV concentrations were determined by Advion Biosciences (Ithaca, NY), in accordance with good laboratory practices, by a validated high-performance liquid chromatography assay with tandem mass spectrometric detection, following solid-phase extraction. The assay demonstrated lower limits of quantitation of 0.01 μg/ml and 0.005 μg/ml for APV and FPV, respectively, when a 50-μl sample aliquot of sodium citrate or sodium EDTA human plasma was used. The calibration curves were linear from 0.01 μg/ml to 10 μg/ml for APV and from 0.005 μg/ml to 1 μg/ml for FPV. The coefficients of determination of the calibration curves were 0.9994 for APV and 0.9987 for FPV when the samples were prepared in sodium citrate plasma. The coefficients of determination of the calibration curves were 0.9990 for APV and 0.9969 for FPV when the samples were prepared in sodium EDTA human plasma. Accuracy and precision quality control (QC) samples were prepared at concentrations of 0.010, 0.035, 1, 8.5, and 10 μg/ml for APV. The accuracy (bias) values calculated from the APV QC samples from all partial validation runs ranged from −2.86% to 1.10%. The precision (coefficient of variation) calculated from the QC samples was ≤4.91%. Both APV and FPV were stable in sodium citrate human plasma for up to 48 h at ambient temperature.
Given that FPV is rapidly and extensively converted to APV with minimal FPV systemic exposures, only APV pharmacokinetic comparisons are presented. The pharmacokinetic analysis of the plasma APV concentration-time data was derived by noncompartmental methods (with WinNonlin, version 4.1 [Pharsight Corporation, Mountain View, CA]). The area under the plasma drug concentration-versus-time curve over the dosing interval at steady state (AUC0-τ) was calculated by a combination of linear (for increasing concentrations) and logarithmic (for decreasing concentrations) trapezoidal methods. The maximum drug concentration (Cmax) observed was the actual value observed. The plasma drug concentration at the end of the dosing interval at steady state (Cτ) was calculated as the average of the predose concentrations on days 11, 12, 13, and 14.
Safety assessments.
A physical examination, including determination of vital signs, was performed at screening. Vital signs were additionally determined prior to dosing on days 1 and 14 of each dosing period.
Adverse events, including the date and time of onset, their severity, and their potential relationship to the study drugs, were assessed starting from day 1 of the first period through the follow-up visit. The following clinical laboratory tests were performed under fasting conditions at screening; on days 1, 7, and 14 during each study period; and at follow-up: hematology, serum chemistries (sodium, potassium, chloride, carbon dioxide, calcium, creatinine, albumin, total protein, glucose, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, creatine phosphokinase, uric acid, blood urea nitrogen, insulin, and fractionated cholesterol and triglycerides), and urinalysis. Insulin resistance (IR) was calculated by using the homeostasis model assessments (HOMA) index, based on fasting glucose and insulin assessments (HOMA IR = [fasting insulin level × fasting glucose level × 0.0555]/22.5) (8). Alpha-1 acid glycoprotein levels were determined only on days 1 and 14 of each regimen period (Focus Technologies, Cypress, CA). A physical examination, including determination of vital signs, was performed at screening and prior to dosing on days 1 and 14 of each RTV dosing period.
Statistical analysis.
Based upon prior pharmacokinetic evaluations of FPV at 1,400 mg plus RTV at 200 mg QD and FPV at 700 mg plus RTV at 100 mg BID with healthy volunteers, an intrasubject standard deviation (SD) of 0.29 was chosen. If an intrasubject SD of 0.29 is assumed, with an 80% power at α equal to 0.05 and an estimated regimen ratio of 1 (13), 30 evaluable subjects would provide a 90% confidence interval (CI) for the ratio of the geometric least-squares (GLS) means of the comparisons of the steady-state plasma AUC0-τ, Cmax, and Cτ values for the FPV-RTV regimen to fall within 0.8 to 1.25 (standard bioequivalence criteria).
Analysis of variance, which considered the sequence, period, and regimen as fixed effects and the subject within the sequence as a random effect, was performed to assess the equivalence of the two FPV-RTV regimens. The ratios of the GLS means and the associated 90% CIs were estimated for the plasma APV pharmacokinetic parameters Cmax, AUC0-τ, and Cτ for FPV at 1,400 mg QD plus RTV at 100 mg QD versus those for FPV at 1,400 mg QD plus RTV at 200 mg QD.
Changes in serum triglyceride levels, total and fractionated cholesterol levels, glucose levels, insulin levels, and HOMA IR between day 1 and day 14 were evaluated for each regimen. Analysis of variance was performed by using SAS PROC MIXED (Cary, NC), with the subject as a random effect and the day as a fixed effect. The estimated least-squares mean differences and P values are reported. Any differences in the incidence of particular adverse events during the 100-mg RTV period versus that during the 200-mg RTV period were not evaluated for statistical significance.
RESULTS
Subject enrollment.
Forty-one subjects (31 men and 10 women) were enrolled and were included in the population for safety analysis. Thirty-six subjects completed both periods of the study and were included in the pharmacokinetic summary population. Six subjects prematurely withdrew due to adverse events (n = 3), loss to follow-up (n = 2; one of these two subjects had completed both periods but never returned for the follow-up visit), and pregnancy (n = 1). Of the 36 study subjects, 22 were Caucasian, 6 were African American, and 13 were Hispanic. The median age was 35 years (range, 18 to 55 years), the median weight was 71 kg (range, 50 to 98 kg), and the median body mass index was 24.5 kg/m2 (range, 19.1 to 30.1 kg/m2).
Pharmacokinetic analysis.
RTV at 100 mg or 200 mg QD in combination with FPV at 1,400 mg QD delivered similar plasma APV AUC0-τ and Cmax values (Table 1; Fig. 1). However, the GLS mean plasma APV Cτ was 38% lower with RTV at 100 mg QD (0.86 μg/ml) than with RTV at 200 mg QD (1.40 μg/ml), with the 90% CI (0.55 to 0.68) for the regimen comparison falling outside of the 90% CI necessary for equivalence (0.80 to 1.25). The lowest reported plasma APV Cτs were 0.42 μg/ml with RTV at 100 mg QD and 0.43 μg/ml with RTV at 200 mg QD.
TABLE 1.
Plasma amprenavir pharmacokinetic parametersa
| Regimen | AUC0-τ (μg · h/ml)
|
Cmax (μg/ml)
|
Cτ (μg/ml)
|
|||
|---|---|---|---|---|---|---|
| Geometric mean (95% CI) | Median (range) | Geometric mean (95% CI) | Median (range) | Geometric mean (95% CI) | Median (range) | |
| FPV at 1,400 mg QD + RTV at 100 mg QD (n = 36) | 66.36 (61.06-72.12) | 62.85 (42.20-157.40) | 7.93 (7.25-8.68) | 7.83 (5.10-15.98) | 0.86 (0.74-1.01) | 0.86 (0.42-2.48) |
| FPV at 1,400 mg QD + RTV at 200 mg QD (n = 36) | 73.80 (66.93-81.37) | 73.70 (46.30-129.00) | 8.17 (7.58-8.81) | 7.85 (4.93-12.14) | 1.40 (1.19-1.66) | 1.49 (0.43-3.30) |
The GLS mean ratios (90% CIs) for AUC0-τ, Cmax, and Cτ were 0.91 (0.86-0.94), 0.97 (0.92-1.03), and 0.62 (0.55-0.68), respectively.
FIG. 1.
Median plasma APV concentrations versus time for the regimen of FPV at 1,400 mg QD plus RTV at 200 mg QD and the regimen of FPV at 1,400 mg QD plus RTV at 100 mg QD. The historical mean APV protein binding-adjusted IC50 for wild-type viral isolates is shown for reference.
Safety and tolerability.
Overall, each regimen was well tolerated, with most adverse events being mild to moderate in nature. Thirty-six of 41 subjects (88%) reported at least one drug-related adverse event. Headache (39%), nausea (34%), and oral paresthesias (34%) were the most commonly reported events. Subjects experienced a higher incidence of adverse drug events while receiving RTV at 200 mg QD than while receiving RTV at 100 mg QD (80% and 68%, respectively), especially nausea (27% and 11%, respectively).
Three subjects prematurely discontinued the study due to adverse drug events, including generalized maculopapular rash with pruritus (one subject after 9 days on FPV at 1,400 mg plus RTV at 200 mg QD), mild elevations in liver function test values (one subject after 14 days on FPV at 1,400 mg plus RTV at 200 mg QD), and mild neutropenia (absolute neutrophil count, 1,200 cells/mm3; one subject after 7 days on FPV at 1,400 mg plus RTV at 100 mg QD). These three adverse events resolved within 18, 35, and 33 days, respectively, after the study drugs were discontinued. No serious (grade 3 or 4) adverse events were reported. One woman became pregnant during the study. The gestational period was of normal duration and was not associated with complications, and the infant showed no abnormalities.
Statistically significant (P < 0.05) increases in fasting total and low-density lipoprotein (LDL) cholesterol and triglyceride concentrations from those at the baseline were observed on day 14 regimens, as were statistically significant decreases in high-density lipoprotein (HDL) cholesterol concentrations (Table 2). Mean fasting serum triglyceride concentrations increased less with FPV at 1,400 mg plus RTV at 100 mg QD than with FPV at 1,400 mg plus RTV at 200 mg QD (+38.86 mg/dl and +61.34 mg/dl, respectively), whereas similar changes in total, HDL, and LDL cholesterol concentrations were observed for both regimens. Cholesterol concentrations returned to normal during the washout and follow-up periods. Mean triglyceride concentrations returned to near baseline concentrations during the washout period. Glucose concentrations decreased significantly (by 3 to 4.5 mg/dl [P < 0.05]) during both regimens between day 1 and day 14 regimens, although insulin levels and HOMA IR did not change significantly.
TABLE 2.
Fasting lipid profiles and change from baseline profilesa
| Fasting lipid parameter | Lipid concn (mg/dl)
|
|||||
|---|---|---|---|---|---|---|
| FPV at 1,400 mg QD + RTV at 100 mg QD (n = 35)
|
FPV at 1,400 mg QD + RTV at 200 mg QD (n = 35)
|
|||||
| Mean (SD)
|
LS mean (SE) change from baseline | Mean (SD)
|
LS mean (SE) change from baseline | |||
| Day 1 | Day 14 | Day 1 | Day 14 | |||
| Total cholesterol | 198 (34) | 211 (34) | 14a (5) | 193 (32) | 208 (34) | 15a (5) |
| LDL cholesterol | 129 (32) | 141 (30) | 13a (5) | 126 (28) | 136 (30) | 10a (4) |
| HDL cholesterol | 46 (12) | 39 (9) | −7a (1) | 45 (14) | 38 (9) | −6a (1) |
| Triglycerides | 116 (70) | 154 (75) | 39a (10) | 108 (52) | 169 (82) | 61a (9) |
Significantly different from the baseline concentration (P < 0.05).
DISCUSSION
Our study demonstrates that a boosting dose of 100 mg of RTV QD, coadministered with FPV at 1,400 mg QD, delivers plasma AUC0-τ and Cmax values equivalent to those delivered by the Food and Drug Administration-approved regimen of FPV at 1,400 mg QD plus RTV at 200 mg QD. The study also shows that the lower boosting dose is associated with a better safety profile, especially a lower incidence of gastrointestinal side effects. Although the GLS mean Cτ was 38% lower for FPV at 1,400 mg plus RTV at 100 mg QD (0.86 μg/ml), it remained sixfold above the mean APV protein binding-adjusted 50% inhibitory concentration (IC50) for wild-type virus (0.146 μg/ml) (Fig. 1) (12) and 2.5-fold above the historical Cτ value observed with unboosted FPV at 1,400 mg BID (18). Even the lowest APV Cτ observed with FPV at 1,400 mg plus RTV at 100 mg QD (0.42 μg/ml) was nearly threefold higher than the mean APV protein binding-adjusted IC50 for wild-type virus (Fig. 2). The GLS mean Cτ for FPV at 1,400 mg plus RTV at 100 mg QD (0.86 μg/ml) was slightly lower than the mean APV protein binding-adjusted IC50 for multiple-PI-resistant HIV isolates (0.90 μg/ml) (12).
FIG. 2.
Individual plasma APV trough concentration changes for subjects receiving FPV at 1,400 mg QD plus RTV at 200 mg QD versus those for subjects receiving FPV at 1,400 mg QD plus RTV at 100 mg QD. The historical APV IC50 for wild-type viral isolates is shown for reference.
The steady-state plasma APV pharmacokinetics observed in the healthy volunteers in this study were comparable to those reported with these regimens in a crossover study with 10 HIV-infected patients (R. Garraffo, T. Lavrut, I. Heripret, M. Serini, H. Carsenti, J. Durant, and P. Dellamonica, 6th Int. Workshop Clin. Pharmacol. HIV Ther., abstr. 5, 2005). In the latter study, the steady-state median APV Cmin produced by FPV at 1,400 mg plus RTV at 100 mg QD was slightly higher (1.08 μg/ml) than the median Cτ in our study, whereas the median APV Cmin produced by FPV at 1,400 mg plus RTV at 200 mg QD was slightly lower (1.28 μg/ml). The use of healthy volunteers instead of HIV-infected patients in our pharmacokinetic study was appropriate because population pharmacokinetic modeling data from four phase I to III clinical studies showed similar APV exposures among healthy and HIV-infected subjects following administration of FPV at 1,400 mg BID and FPV plus RTV at 200 mg QD (Y. Kim, C. Hu, M. Wire, K. Moore, and M. Sale, 5th Int. Workshop Clin. Pharmacol. HIV Ther., abstr. 7.5, 2004).
Our study showed bioequivalence between the two RTV dose regimens for the APV AUC and Cmax and a 38% lower Cτ for FPV at 1,400 mg plus RTV at 100 mg QD. In contrast, a study by Kurowski (1st IAS Conf. HIV Pathogenesis Treatment) evaluated plasma APV pharmacokinetics with APV at 1,200 mg plus RTV at 100 mg QD for 7 days in period 1, immediately followed by APV at 1,200 mg plus RTV at 200 mg QD in period 2. Although the AUC and Cmax ratios in that study were close to a value of 1.0, the CIs for these parameters were too wide to demonstrate bioequivalence. Kurowski reported only a 13% lower Cτ for RTV at 100 mg daily, but the CI was wide and included a value of 1.0. Other limitations of the characteristics of the Kurowski study compared to those of our study were the use of a single sequence of study regimens without a washout period (in contrast to the use of randomized sequences with a washout period in the present study), the relatively short duration of dosing for each study regimen (7 and 14 days in the Kurowski and present studies, respectively), and the relatively small sample size (12 and 36 subjects in the Kurowski and present studies, respectively). Given that plasma APV exposure is known to be time variant, the effects of continued dosing may have confounded the effects of the higher ritonavir dose in the second period of the study.
Various PIs appear to differ with respect to the minimum RTV dose necessary to provide maximal boosting. For saquinavir at a dose of 1,200 mg QD, plasma saquinavir exposure did not appear to be different when saquinavir was coadministered with RTV at 100 mg and when it was coadministered with RTV at 200 mg (7). For indinavir at a dose of 800 mg QD, plasma indinavir exposure appeared to be 15 to 25% lower with RTV at 100 mg than with RTV at 200 mg (A. Saah, G. Winchell, M. Seniuk, M. Nessly, and P. Deutsch, 39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 329, 1999). Frequency of administration may have an impact on the optimal RTV dose necessary for maximal boosting. For BID high-dose FPV (1,400 mg), coadministration of RTV at 200 mg BID resulted in an 18% lower plasma APV exposure compared to that obtained with BID high-dose FPV in combination with RTV at 100 mg BID (15). For lopinavir at 400 mg BID, RTV at 200 mg BID appeared to result in a higher plasma lopinavir exposure compared to that obtained with coadministration of RTV at 100 mg BID (9). For BID saquinavir (soft gelatin capsule formulation), RTV at 300 mg resulted in a higher plasma saquinavir exposure compared to that obtained with coadministration of RTV at 200 mg (1).
Our pharmacokinetic findings for APV at 1,400 mg plus RTV at 200 mg QD are consistent with those reported earlier with a 14-day course of this regimen in one study (APV10009) (17), where the GLS mean steady-state AUC0-τ was 69.4 μg · h/ml, Cτ was 1.45 μg/ml, and Cmax was 7.24 μg/ml for 22 healthy volunteers.
The finding of fewer gastrointestinal adverse events with RTV at 100 mg QD than with RTV at 200 mg QD was expected in view of earlier reports of an increase in the number of adverse events with daily RTV doses exceeding 200 mg (2). Fewer dyslipidemic effects with RTV at 100 mg QD were also expected, because RTV's effect on lipids is dose related (2). Most PIs are associated with at least a slight elevation in lipids, with the fewest effects being observed in studies of FPV and atazanavir (4). Although increases in the GLS mean triglyceride, total cholesterol, and LDL cholesterol levels and decreases in HDL cholesterol levels did achieve statistical significance for our study group as a whole during the 14-day dosing period, these changes were unlikely to be clinically significant because most serum lipid values stayed within the normal limits for each lipid parameter. Whether the short-term benefits on triglyceride levels of RTV at 100 mg QD over those of RTV at 200 mg QD observed in this study are maintained with chronic administration has yet to be determined. Longer-term data reported in the SOLO/APV30005 study suggest that over 120 weeks, favorable HDL cholesterol level increases appear in antiretroviral therapy-naïve patients whose initial treatment is FPV-RTV plus abacavir-lamivudine (J. Flamm, M. Lorber, D. Thomas, N. Givens, and T. Stark, 6th Int. Workshop Adverse Drug Reactions Lipodystrophy HIV, abstr. L-786, 2004), just as they have been observed over 120 weeks in such patients whose initial treatment was unboosted FPV plus abacavir-lamivudine (J. Nadler, A. Rodriguez-French, P. Wannamaker, S. Tomkins, and T. Stark, 44th Intersci. Conf. Antimicrob. Agents Chemother., abstr. H-156, 2004). The statistically significant decrease in glucose levels in this study is unlikely to be clinically important, because no changes in insulin levels or HOMA IR were observed. An earlier study (the COL30309 study) of the metabolic effects of APV over 48 weeks of treatment reported that APV does not significantly affect serum glucose levels or insulin resistance (3).
The results from this study suggest that coadministration of FPV at 1,400 mg with a reduced RTV dose of 100 mg QD has a better short-term adverse event and triglyceride profile than standard dosing with FPV at 1,400 mg plus RTV at 200 mg QD and that the reduced-dose RTV regimen produces sufficient plasma APV exposures for the treatment of HIV-1-infected, PI treatment-naïve patients. The better tolerability of the boosting dose of RTV at 100 mg QD, the lower pill burden involved for RTV at 100 mg relative to that involved for RTV at 200 mg QD, and the convenience of QD dosing are all factors that would be expected to enhance patient adherence to an FPV- and RTV-containing therapy (11). In view of these findings, further investigation of the efficacy, safety, and resistance profile of FPV at 1,400 mg plus RTV at 100 mg QD in PI-treatment naïve, HIV-infected patients is under way.
Acknowledgments
We thank the subjects who participated in this study and the staff of the PPD Phase 1 Unit in Austin, TX, for making the study possible. We also thank Shuching Shaw and Mei-jen Liu for assistance with the statistical analysis and Gary Pakes for assistance with writing the manuscript.
Footnotes
Published ahead of print on 6 November 2006.
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