Abstract
Eltrombopag is an orally bioavailable thrombopoietin receptor agonist that is approved for the treatment of chronic idiopathic thrombocytopenic purpura. It is being developed for other medical disorders that are associated with thrombocytopenia. Patients with human immunodeficiency virus (HIV) may suffer from thrombocytopenia as a result of their HIV disease or coinfection with hepatitis C virus (HCV). HIV medications, particularly ritonavir (RTV)-boosted HIV protease inhibitors, are involved in many drug interactions. This study evaluated the potential drug-drug interaction between eltrombopag and lopinavir (LPV)/RTV. Forty healthy adult subjects enrolled in this open-label, three-period, single-sequence crossover study received a single 100-mg dose of eltrombopag (period 1), LPV/RTV at 400/100 mg twice daily (BID) for 14 days (period 2), and LPV/RTV at 400/100 mg BID (2 doses) with a single 100-mg dose of eltrombopag administered with the morning LPV/RTV dose (period 3). There was a 3-day washout between periods 1 and 2 and no washout between periods 2 and 3. Serial pharmacokinetic samples were collected during 72 h in periods 1 and 3 and during 12 h in period 2. The coadministration of 400/100 mg LPV/RTV BID with a single dose of 100 mg eltrombopag decreased the plasma eltrombopag area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-∞) by 17%, on average, with no change in plasma LPV/RTV exposure. Adverse events (AEs) reported in period 2 were consistent with known LPV/RTV AEs, such as diarrhea, abdominal pain, nausea, vomiting, rash, and fatigue. No subjects withdrew due to AEs, and no serious AEs were reported. These study results suggest that platelet counts should be monitored and the eltrombopag dose adjusted accordingly if LPV/RTV therapy is initiated or discontinued.
INTRODUCTION
Eltrombopag (Promacta) is the first oral, nonpeptide, thrombopoietin-receptor agonist; it induces the proliferation and differentiation of normal marrow progenitors into megakaryocytes, resulting in increased circulating platelet counts (11, 16). Eltrombopag is approved for the treatment of immune thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) (6, 7, 8) and is being developed for other medical disorders associated with immune thrombocytopenia, such as chemotherapy-induced thrombocytopenia (17) and hepatitis C virus (HCV) infection (2, 23).
Patients with human immunodeficiency virus (HIV) may suffer from immune thrombocytopenia as a result of their HIV disease or coinfection with HCV. In a study of 391 patients with controlled HIV infection (baseline CD4+ cell count of >450 cells/mm3 and plasma HIV-1 RNA of <400 copies/ml) receiving antiviral therapy (95% received highly active antiretroviral therapy [HAART]), median (interquartile range [IQR]), baseline platelet counts were 243 (206, 283) × 109/liter (4). Following randomization, 9.8% of patients who stayed on their current antiretroviral therapy and 25.4% of patients who initiated intermittent treatment interruption experienced thrombocytopenia (platelet count of <150 ×109/liter) during the 96-week trial; severe thrombocytopenia (platelet count of <50 × 109/liter) occurred in 1% of patients who stayed on their current therapy and 4.6% of patients who initiated intermittent treatment interruption (4). Thrombocytopenia in patients with HIV has been associated with HCV coinfection, cirrhosis, low CD4 lymphocyte counts, and plasma HIV-1 RNA of >400 copies/ml (4, 22). In patients with HIV, thrombocytopenia may result from increased platelet destruction by autoantibodies formed by immune activation, decreased platelet production due to the HIV infection of megakaryocytes, bone marrow suppressive medication use, and concomitant diseases, such as opportunistic infections, malignancies, and HCV infection (24). Interferon-based HCV therapy may be successful for patients with HIV/HCV; however, this therapy is associated with thrombocytopenia that can necessitate interferon dose reduction or a temporary treatment interruption until platelet counts return to pretreatment levels. Eltrombopag has demonstrated the ability to increase platelet counts in patients with HCV (2, 23), therefore eltrombopag is a candidate for testing in HIV-infected and HIV/HCV coinfected patients.
Ritonavir-boosted protease inhibitors (PIs) play an important role in the treatment of HIV because of their potency, durable antiviral activity, and high barrier to resistance. Lopinavir/ritonavir (LPV/RTV; Kaletra) is an HIV PI widely used in combination antiretroviral therapy regimens and, like other ritonavir-boosted PIs, is involved in many drug-drug interactions (1).
Plasma LPV/RTV exposures are reduced when coadministered with potent CYP3A4 inducers, such as rifampin and efavirenz (14, 20). Clinical drug-drug interaction studies have demonstrated that LPV/RTV inhibits CYP3A4 and CYP2D6 and induces CYP2C9, CYP2C19, and CYP1A2 (12, 21, 28, 29). LPV/RTV has demonstrated the potential to both inhibit and induce UDP-glucuronosyltransferases (UGTs) (9, 25, 26). In addition to drug interactions mediated through drug-metabolizing enzymes, LPV/RTV has demonstrated drug transporter-mediated interactions. For example, the increased plasma rosuvastatin and pravastatin concentrations observed with LPV/RTV coadministration involve SLCO1B1 (OATP1B1) and ABCG2 (BCRP) transporters (19). LPV/RTV also inhibits P-glycoprotein (Pgp) (28).
The net effects of LPV/RTV on drug transporters and metabolizing enzymes results in numerous drug interactions, which may be difficult to predict. Absorbed eltrombopag is extensively metabolized through oxidation and glucuronidation; CYP1A2, CYP2C8, UGT1A1, and UGT1A3 were the enzymes identified as being responsible for eltrombopag metabolism in vitro (13). Eltrombopag is an ABCG2 (BCRP) substrate (13). The coadministration of LPV/RTV with eltrombopag could alter plasma eltrombopag exposure through metabolic induction or ABCG2 (BCRP) inhibition. No impact of eltrombopag on plasma LPV or RTV concentrations was expected, as eltrombopag does not inhibit or induce CYP enzymes (15). Although eltrombopag inhibits SLCO1B1 (OATP1B1) and ABCG2 (BCRP) transporters and UGTs (3, 13), these mechanisms of interaction were not predicted to alter plasma LPV/RTV exposure.
It is important to be aware of the potential drug-drug interactions with commonly prescribed HIV PIs, such as LPV/RTV, due to the induction or inhibition of numerous drug-metabolizing enzymes and transporters. Therefore, this study was designed to evaluate the potential drug-drug interaction between eltrombopag and LPV/RTV to guide the dosing of this combination.
MATERIALS AND METHODS
Subjects.
Healthy males and females were enrolled at the Buffalo Clinical Research Center in Buffalo, NY. Subjects were recruited via an institutional review board (IRB)-approved letter and advertisement; subjects in the study site's database received the letter and advertisement, and the advertisement was posted to the clinical site's website. Subjects were paid for participation in the study. Subjects were between the ages of 18 and 64 years, inclusive, with a body mass index (BMI) of 18.5 to 29.9 kg/m2 and no clinically significant abnormality based on medical history, physical examination, clinical laboratory tests, and electrocardiogram. Subjects must have tested negative for HIV, hepatitis B virus (HBV), or HCV at the time of screening. Female subjects of childbearing potential were required to have a negative β-human chorionic gonadotropin pregnancy test to be eligible for participation in the study.
Subjects were excluded from the study if they reported a history of deep-vein thrombosis or other thromboembolic event(s), clotting factor abnormalities associated with hypercoagulability, or thrombocytopenia or bleeding due to abnormal platelet count/function. Elevated blood pressure (systolic, >140 mmHg; diastolic, >85 mmHg) or prolonged QT interval (corrected by Bazett's formula) (females, >450 ms; males, >430 ms) at screening also excluded subjects from the study. Subjects with a history of cardiac abnormalities, such as atrial fibrillation, mitral valve prolapse, significant heart murmur, or vascular bruit, were also excluded. Furthermore, potential subjects were excluded if they had a history of Gilbert's syndrome, history of alcohol dependency within 12 months, excessive alcohol consumption, or regular tobacco use within 6 months of screening. The anticipated use of prescription or nonprescription medication(s) during the study also excluded subjects from study participation unless the investigator and sponsor felt that the medication(s) would not interfere with the study procedures or compromise the safety of the subject. Female subjects currently receiving hormonal contraception or hormone replacement therapy were also excluded. All subjects provided written informed consent prior to enrollment in the study. The study was conducted in accordance with the standards of the site's IRB and the principles of good clinical practice, all applicable regulatory requirements, the Code of Federal Regulations, and the Declaration of Helsinki.
Study design.
This phase I, open-label, 3-period, single-sequence crossover study conducted in healthy subjects was designed to evaluate the potential drug-drug interaction between eltrombopag and LPV/RTV. Subjects received a single oral dose of 100 mg eltrombopag in period 1, 400/100 mg LPV/RTV BID for 14 days in period 2, and 400/100 mg LPV/RTV BID for 1 day with a single dose of 100 mg eltrombopag administered with the morning LPV/RTV dose in period 3. There was a 3-day washout between periods 1 and 2 to allow for 72-h serial pharmacokinetic (PK) sampling. There was no washout between periods 2 and 3 to allow for the assessment of repeated-dose LPV/RTV effects on eltrombopag PK. Subjects were required to fast for a minimum of 10 h prior to and for 4 h after morning doses of study drugs on serial PK sampling days. Subjects were admitted to the clinical research unit (CRU) from the day prior to dosing (day −1) in period 1 and discharged following the administration of the first dose of LPV/RTV in period 2. Subjects were admitted to the CRU again on day 13 of period 2 and discharged following the collection of the 72-h PK sample in period 3. Subjects also attended the CRU on days 8 and 12 of period 2. The total duration of subject participation in the study was approximately 2 months, including screening within 28 days prior to enrollment, three treatment periods, and a final follow-up visit within 10 to 14 days after the last dose of study drugs.
PK sampling and drug concentration assays.
Serial blood samples were collected via the forearm vein into EDTA anticoagulation tubes. Blood samples for the determination of plasma eltrombopag concentrations were collected predose and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, and 72 h after dosing following single-dose eltrombopag administration in periods 1 and 3. Blood samples for the determination of plasma LPV and RTV concentrations were collected predose and at 1, 2, 3, 4, 5, 6, 8, and 12 h after dosing following the repeated-dose administration of LPV/RTV on day 14 of period 2 and day 1 of period 3. Single predose PK samples were also collected on days 12 and 13 of period 2 to assess the achievement of LPV/RTV steady state.
Eltrombopag plasma PK samples were assayed for eltrombopag using a validated analytical method based on protein precipitation, followed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis (3).
LPV and RTV were extracted from plasma samples using acetonitrile containing [2H213C3]lopinavir and [2H213C315N]ritonavir as internal standards. Extracts were then analyzed by HPLC-MS/MS using a TurboIonSpray (Applied Biosystems, Foster City, CA) interface with negative-ion multiple-reaction monitoring (m/z for LPV, 629 to 447; LPV internal standard, 634 to 452; m/z for RTV, 721 to 140; RTV internal standard, 727 to 140). The lower limit of quantification for the assay was 20 ng/ml for LPV and 10 ng/ml for RTV, and the higher limit of quantification was 20,000 ng/ml for LPV and 10,000 ng/ml for RTV. Imprecision and inaccuracy between assays were <15%.
Safety assessment.
Safety was assessed throughout the study by the measurement of vital signs and by clinical laboratory tests. Subjects were monitored for adverse events (AEs) throughout the study. The frequency, severity, and relationship to treatment of AEs that occurred during study treatment and the follow-up period of 10 to 14 days after treatment were evaluated. AEs were summarized by treatment.
Pharmacokinetic analysis.
Pharmacokinetic calculations were based on actual sample collection times recorded. Pharmacokinetic parameters were calculated for each subject using standard noncompartmental methods (WinNonlin, version 5.2; Pharsight Corporation, Mountain View, CA). Eltrombopag PK parameters, including area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC0-t), AUC from time zero extrapolated to infinity (AUC0-∞), percent AUC0-∞ obtained by extrapolation (%AUCex), maximum concentration (Cmax), time to Cmax (Tmax), apparent clearance (CLF), and half-life (t1/2), were determined from single-dose plasma concentration-time data. LPV and RTV PK parameters, Cmax, Tmax, AUC over the dosing interval (AUC0-τ), and concentration at the end of the dosing interval (Cτ) were determined from repeated-dose plasma concentration-time data.
Statistical analysis.
Statistical analyses were performed using the SAS/STAT module of SAS, version 9.1.3 (SAS Institute, Cary, NC). Plasma eltrombopag, LPV, and RTV PK parameters were natural log transformed before analysis by mixed-effect analysis of variance (ANOVA), fitting terms for treatment as a fixed effect and subject as a random effect. Point estimates and 90% confidence intervals (CI) for the differences between eltrombopag in combination with LPV/RTV (period 3) and eltrombopag alone (period 1) and between LPV/RTV in combination with eltrombopag (period 3) and LPV/RTV alone (period 2) were constructed using the appropriate error terms. Point and 90% CI estimates on the log scale were back transformed to provide point and 90% CI estimates for the treatment ratios.
The analysis of Cτ on days 12 to 14 evaluated whether the steady state of LPV/RTV was achieved in period 2. Following natural log transformation, a mixed-effect ANOVA model was fitted with day as a fixed and continuous effect and subject as a random effect. The coefficient for the slope and the corresponding 90% CI were computed.
RESULTS
Demographic and baseline characteristics.
This study enrolled 40 healthy subjects (23 females, 17 males). The majority of subjects were white Caucasian (30 of 40 subjects; 75%), 9 of 40 subjects (23%) were African American, and 1 subject was central/south Asian. The mean (range) age was 33 years (19 to 59 years). The mean weight (range) was 72.4 kg (48.1 to 97.5 kg), and the mean (range) BMI was 25.3 kg/m2 (19.3 to 30.8 kg/m2). All subjects were included in the safety and PK analysis.
Pharmacokinetics.
The coadministration of repeat doses of 400/100 mg LPV/RTV BID with a single dose of 100 mg eltrombopag resulted in no change in plasma eltrombopag Cmax, an average reduction in AUC0-∞ of 17%, and an average reduction in t1/2 of 41% (Table 1 and Fig. 1), suggesting that LPV/RTV is a weak inducer of eltrombopag clearance. The plasma eltrombopag CLF increased an average of 21% when coadministered with LPV/RTV (Table 1). There was no impact of a single 100-mg dose of eltrombopag on repeated-dose plasma LPV or RTV PK (Table 2 and Fig. 2). The LPV and RTV steady state was reached by day 14, since the 90% CI of the slope estimates from the linear regressions of log-transformed plasma LPV and RTV predose concentrations collected on days 12, 13, and 14 included zero; the slope (90% CI) for LPV was 0.002 (−0.079, 0.082) and for RTV was −0.088 (−0.196, 0.020).
Table 1.
Summary of plasma eltrombopag pharmacokinetic parameters following single-dose administration (n = 40)
| Parameter | Result fora: |
GLS mean ratiob | |
|---|---|---|---|
| Eltrombopag | Eltrombopag with LPV/RTV | ||
| Cmax (μg/ml) | 11.1 (9.7, 12.6) | 11.5 (10.1, 13.0) | 1.04 (0.915, 1.173) |
| AUC0-t (μg · h/ml) | 126 (111, 145) | 112 (96, 129) | 0.88 (0.781, 0.990) |
| AUC0-∞ (μg · h/ml) | 140 (121, 162) | 116 (100, 134) | 0.83 (0.734, 0.934) |
| CLF (ml/h) | 716 (619, 829) | 865 (746, 1003) | 1.21 (1.071, 1.362) |
| Tmax (h) | 4.00 (2.00-6.00) | 4.00 (2.00-6.02) | NA |
| t1/2 (h) | 23.6 (21.4, 26.0) | 13.9 (12.4, 15.5) | 0.59 (0.546, 0.635) |
The summary statistics are presented as geometric mean values with 95% CIs in parentheses, except for Tmax, which has summary statistics presented as medians (minimum, maximum).
The data are presented as geometric least-squares mean ratios (90% CIs). NA, not applicable.
Fig 1.
Median plasma eltrombopag concentration-time profiles. ♢, Eltrombopag at 100 mg (n = 40); ♦, eltrombopag at 100 mg plus 400/100 mg LPV/RTV twice daily (n = 40).
Table 2.
Summary of plasma lopinavir and ritonavir pharmacokinetic parameters following repeated-dose administration (n = 40)
| Drug and parameter | Result fora: |
GLS mean ratiob | |
|---|---|---|---|
| LPV/RTV | Eltrombopag with LPV/RTV | ||
| Lopinavir | |||
| Cmax (μg/ml) | 10.7 (9.9, 11.6) | 10.5 (9.7, 11.4) | 0.98 (0.943, 1.019) |
| AUC0-τ (μg · h/ml) | 92.6 (84.4, 101.6) | 91.0 (82.9, 99.9) | 0.98 (0.945, 1.021) |
| Cτ (μg/ml) | 4.08 (3.40, 4.89) | 4.11 (3.48, 4.84) | 1.01 (0.940, 1.078) |
| CLF (liters/h) | 4.32 (3.94, 4.74) | 4.40 (4.00, 4.83) | 1.02 (0.979, 1.058) |
| Tmax (h) | 3.00 (2.00–5.03) | 3.00 (1.00–5.00) | NA |
| Ritonavir | |||
| Cmax (μg/ml) | 0.911 (0.788, 1.05) | 0.841 (0.718, 0.984) | 0.92 (0.835, 1.020) |
| AUC0-τ (μg · h/ml) | 4.84 (4.21, 5.56) | 4.66 (4.05, 5.35) | 0.96 (0.885, 1.046) |
| Cτ (μg/ml) | 0.086 (0.072, 0.102) | 0.089 (0.076, 0.105) | 1.04 (0.971, 1.123) |
| CLF (liters/h) | 20.7 (18.0, 23.8) | 21.5 (18.7, 24.7) | 1.04 (0.956, 1.130) |
| Tmax (h) | 3.00 (2.00–5.00) | 3.00 (1.00–5.00) | NA |
The summary statistics are presented as geometric mean values with 95% CIs in parentheses, except for Tmax, which has summary statistics presented as medians (minimum, maximum).
The data are presented as geometric least-squares mean ratios (90% CIs). NA, not applicable.
Fig 2.
Median plasma lopinavir and ritonavir concentration-time profiles. ■, Lopinavir in 400/100-mg LPV/RTV doses twice daily (n = 40); □, lopinavir in 400/100-mg LPV/RTV doses twice daily plus 100 mg eltrombopag (n = 40); Δ, ritonavir in 400/100-mg LPV/RTV doses twice daily (n = 40); ▲, ritonavir in 400/100-mg LPV/RTV doses twice daily plus 100 mg eltrombopag (n = 40).
Safety.
Ten subjects received acetaminophen for headaches (n = 7), menstrual cramps (n = 1), headache and fever (n = 1), or cold symptoms (n = 1). The subject with cold symptoms also took cough drops. One subject used docosanol for cold sores. Sixty-six AEs were reported by 15 (38%) subjects in period 1, 37 (93%) subjects in period 2, and 14 (35%) subjects in period 3 (Table 3). All AEs reported were mild in intensity, with the exception of one moderate event of headache and one moderate event of abdominal pain. The majority of AEs were reported in period 2, and the AEs were consistent with the established safety profile of LPV/RTV. In period 2, the most frequently reported AEs were diarrhea (26 subjects [65%]) and nausea (17 subjects [43%]). No subjects discontinued the study due to AEs, and no serious AEs were reported during this study.
Table 3.
Summary of adverse events (n = 40)a
| Adverse event | Eltrombopag | LPV/RTV | Eltrombopag with LPV/RTV |
|---|---|---|---|
| Any | 15 (38) | 37 (93) | 14 (35) |
| Drug related | 10 (25) | 37 (93) | 9 (23) |
| Ocular hyperemia | 0 [0] | 0 [0] | 2 (5) [2 (5)] |
| Diarrhea | 3 (8) [2 (5)] | 26 (65) [26 (65)] | 3 (8) [3 (8)] |
| Nausea | 5 (13) [4 (10)] | 17 (43) [17 (43)] | 0 [0] |
| Abdominal pain | 2 (5) [1 (3)] | 8 (20) [8 (20)] | 0 [0] |
| Flatulence | 2 (5) [1 (3)] | 5 (13) [5 (13)] | 0 [0] |
| Vomiting | 1 (3) [1 (3)] | 4 (10) [4 (10)] | 0 [0] |
| Fatigue | 1 (3) [1 (3)] | 5 (13) [5 (13)] | 1 (3) [1 (3)] |
| Edema | 0 [0] | [2 (5)] | 0 [0] |
| Stomach discomfort | 0 [0] | 2 (5) [0] | 1 (3) |
| Nasopharyngitis | 0 [0] | 3 (8) [0] | 1 (3) |
| Decreased appetite | 0 [0] | 3 (8) [0] | 0 [0] |
| Headache | 5 (13) [4 (10)] | 7 (18) [6 (15)] | 2 (5) [1 (3)] |
| Dysgeusia | 1 (3) [1 (3)] | 2 (5) [2 (5)] | 0 [0] |
| Rash | 0 [0] | 2 (5) [2 (5)] | 0 [0] |
| Flushing | 0 [0] | 2 (5) [2 (5)] | 0 [0] |
Data are presented as number (%) of subjects reporting AEs. Data in brackets are numbers (%) of subjects reporting drug-related AEs.
As expected, total cholesterol and triglycerides increased during LPV/RTV treatment: 30% of healthy subjects shifted from normal total cholesterol values to cholesterol values above the upper limit of normal (ULN), and 23% of healthy subjects shifted from normal triglyceride values to triglyceride values above the ULN by day 14 of period 2. All total cholesterol values were grade 1 (≤1.3-fold ULN), except one subject who had a grade 2 elevation (1.38-fold ULN). All triglyceride concentrations were grade 1 (<400 mg/dl). No clinically significant changes in vital signs or clinical laboratory results were reported in any treatment period during this study.
DISCUSSION
Eltrombopag has not been studied for the treatment of thrombocytopenia in HIV-infected or coinfected HIV/HCV patients, but there is potential for its use in HCV/HIV-infected patients if eltrombopag is shown to be safe and efficacious in the HCV patient population. Eltrombopag has a low potential for PK interactions with HIV medications because it is metabolized through multiple pathways and does not inhibit or induce metabolizing enzymes. However, given that HIV protease inhibitors such as LPV/RTV are widely used in HIV treatment and are involved in many drug-drug interactions, this study was conducted to evaluate potential interactions between eltrombopag and LPV/RTV to guide the dosing of this combination.
Because LPV/RTV has known metabolic induction effects, which are observed upon repeat dosing, LPV/RTV was dosed for 2 weeks in this study. In contrast, eltrombopag has not demonstrated the potential to inhibit or induce drug-metabolizing enzymes and has time-invariant PK. Therefore, it was appropriate to administer eltrombopag as a single dose. To facilitate the different dosing durations, a single-sequence design was implemented whereby eltrombopag was administered alone in period 1, LPV/RTV was administered alone in period 2, and LPV/RTV and eltrombopag were coadministered in period 3, with no washout between periods 2 and 3.
The coadministration of repeated doses of 400/100 mg LPV/RTV BID with a single dose of 100 mg eltrombopag resulted in no change in plasma eltrombopag Cmax, an average 17% reduction in AUC0-∞, and an average 41% reduction in t1/2, suggesting that LPV/RTV is a weak inducer of eltrombopag clearance. Because LPV/RTV has previously demonstrated the induction of CYP1A2 and UGTs (25, 26, 29), enzymes that are involved in eltrombopag metabolism, the 21% increase in the apparent clearance of eltrombopag may have resulted from the induction of either or both of these enzymes. The goal of eltrombopag therapy is to maintain platelet counts above a minimum threshold, and a small reduction in plasma eltrombopag exposure is not expected to reduce platelet counts below this threshold in the majority of patients. Platelet counts are routinely monitored during eltrombopag therapy, and the dose is adjusted as appropriate based on platelet count; therefore, for individual subjects whose platelet counts fall below the threshold while receiving concomitant LPV/RTV, dose adjustment is a practical way to manage the interaction. As expected, there was no impact of eltrombopag on plasma LPV or RTV PK. Because LPV/RTV is involved in many clinical drug-drug interactions, the relatively small interaction observed between eltrombopag and LPV/RTV confirms previous data suggesting that eltrombopag has a low potential for clinically significant drug-drug interactions.
Nelfinavir, fosamprenavir/RTV, and tipranavir/RTV are other HIV PIs that have demonstrated induction effects on CYP1A2 substrates, with potency that is relatively similar to that of RTV or LPV/RTV (5, 10, 18). Darunavir, saquinavir, and indinavir are not known inhibitors or inducers of CYP1A2. The impact of HIV PIs on CYP2C8 has not been well described. Atazanavir could increase plasma eltrombopag concentrations through UGT inhibition; however, UGT inhibition interactions are typically of small magnitude, particularly when a drug is also metabolized by other pathways (27). In addition, atazanavir is not typically used in patients with liver disease given its propensity to increase unconjugated bilirubin.
The AEs reported following single-dose eltrombopag (period 1) were consistent with those previously reported for eltrombopag. Subjects receiving LPV/RTV alone in period 2 reported the majority of AEs, which were consistent with known LPV/RTV AEs. When eltrombopag was added to LPV/RTV in period 3, the AEs reported remained consistent with previously reported events with eltrombopag alone. Given the short duration of dosing and conduct in a healthy adult population, the safety data collected in this study may not reflect the safety profile of the long-term coadministration of eltrombopag and LPV/RTV in patients infected with HIV or HIV/HCV.
In conclusion, the coadministration of LPV/RTV decreased the average plasma eltrombopag AUC0-τ by 17%. These study results suggest that platelet counts should be monitored and the eltrombopag dose adjusted accordingly if LPV/RTV therapy is initiated or discontinued during treatment with eltrombopag.
ACKNOWLEDGMENTS
This research was sponsored by GlaxoSmithKline, Inc.
We thank Robert Blum and Christian Lates of the Buffalo Clinical Research Center, Buffalo, NY, for their contributions in the conduct of this study. We also acknowledge Julienne Orr of Modoc Research Services Inc., who provided medical writing services on behalf of GlaxoSmithKline Inc.
Footnotes
Published ahead of print 5 May 2012
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