Krishna, Gopal PhD; Moton, A PharmD; Ma, L MS; Martinho, M MS; Seiberling, M MD; McLeod, J MD
Patients with HIV or AIDS are immunocompromised and thus are at increased risk for opportunistic fungal infections. Although highly active antiretroviral therapy with protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) has reduced the incidence of opportunistic infections in some patients with HIV/AIDS, they remain an important cause of morbidity and mortality in others.1 Azole antifungal agents are often used in the prophylaxis and treatment of fungal infections, and the potential for drug-drug interactions must be considered when these agents are coadministered with antiretrovirals.2,3
Posaconazole (Noxafil; Schering-Plough, Kenilworth, NJ), an extended-spectrum triazole with activity against many medically important fungi, including Candida, Aspergillus, Zygomycetes, Fusarium, and Cryptococcus neoformans,4,5 has demonstrated efficacy as antifungal prophylaxis and treatment.6-11 As with other azole antifungal agents, posaconazole inhibits the activity of the hepatic cytochrome P450 (CYP450) isoform, CYP3A4, which can increase the plasma concentration and exposure of drugs metabolized by this enzyme.12 However, posaconazole does not inhibit the CYP450 isoforms CYP1A2, 2C8/9, 2D6, or 2E1,12 which indicates that posaconazole has a lower drug interaction potential than other azole antifungals including voriconazole and itraconazole. In contrast to other azoles, oxidation by phase 1 enzymes is a minor pathway for posaconazole; instead, its metabolism is mediated primarily by uridine diphosphate glucuronosyltransferase (UGT) 1A4.13,14
Highly active antiretroviral therapy is the cornerstone of the treatment strategy to reduce overall mortality among patients with HIV/AIDS. Because combination antiretroviral therapy with an antifungal agent is a common treatment strategy for patients with HIV/AIDS and severe immune suppression,1 we analyzed the drug interaction potential of posaconazole with 3 commonly used antiretrovirals, atazanavir (ATV) (Reyataz; Bristol-Myers Squibb, Princeton, NJ), ritonavir (Norvir; Abbott Laboratories, Chicago, IL), and efavirenz (Sustiva; Bristol-Myers Squibb). ATV, an azapeptide HIV-1 protease inhibitor, is metabolized primarily by hepatic CYP3A4 but is also an inhibitor of CYP3A4 activity and UGT1A1 activity.15 For full effectiveness in the treatment of HIV, patients who are treated with ATV are usually also treated with ritonavir. Ritonavir is a peptidomimetic inhibitor of HIV-1 and HIV-2 proteases and an inhibitor of CYP3A4 activity and substrate for CYP3A4.16 Efavirenz, an HIV-1-specific NNRTI, is an inducer and an inhibitor of CYP3A4 and also an inducer of UGT.17-20
The aim of this study was to evaluate the pharmacokinetic interactions between posaconazole and ATV, when administered with and without ritonavir, and between posaconazole and efavirenz.
This was a phase 1, open-label, 2-part, randomized (1:1) crossover, drug interaction study conducted at a single center in Switzerland in conformance with Good Clinical Practices. In part 1, pharmacokinetic interactions between posaconazole and ATV (alone and with ritonavir) were analyzed; in part 2, pharmacokinetic interactions between posaconazole and efavirenz were analyzed.
Twelve healthy adults were randomized (1:1) to 2 treatment arms. In arm 1, 6 subjects received ATV and ritonavir for 7 days; ATV, ritonavir, and posaconazole for 7 days; no drugs for a 28-day washout period; ATV for 7 days; and then ATV and posaconazole for 7 days. In arm 2, 6 subjects received drugs in the reverse sequence. Dosages were oral ATV 300 mg once daily, oral ritonavir 100 mg once daily, and oral posaconazole 400 mg twice daily. Subjects were confined for 12 hours before dosing. Duration of study was 59 days.
Blood samples were collected at 0, 1, 2, 4, 8, 12, and 24 hours for ATV and/or ritonavir plasma level determination on days 7, 14, 49, and 56. Blood samples were collected for determination of posaconazole plasma levels at 24, 48, and 72 hours after the last posaconazole dose on days 15, 16, 17, 57, 58, and 59.
Seventeen healthy adults were randomized (1:1) to 2 treatment arms. In arm 1, 8 subjects received efavirenz for 10 days, efavirenz and posaconazole for 10 days, no drugs for a 28-day washout period, and then posaconazole for 10 days. In arm 2, 9 subjects received posaconazole for 10 days, efavirenz and posaconazole for 10 days, no drugs for a 28-day washout period, and then efavirenz for 10 days. Dosages were oral efavirenz 400 mg once daily and oral posaconazole 400 mg twice daily. All subjects were confined for 12 hours before dosing. Duration of study was 60 days.
For arm 1, blood samples were collected at 0, 1, 2, 4, 8, 12, and 24 hours for efavirenz plasma level determination on days 10 and 20 (15 total samples per subject) and for determination of posaconazole plasma levels on days 20 and 58. For arm 2, blood samples were collected at 0, 1, 2, 4, 8, 12, and 24 hours for posaconazole analysis on days 10 and 20 (14 total samples per subject) and for efavirenz analysis on days 20 and 58.
For both study parts, all plasma and blood samples were assayed using a validated liquid chromatography with tandem mass spectrometric detection method for posaconazole (Schering-Plough Research Institute, Summit, NJ),21 ATV, and ritonavir (Covance, Indianapolis, IN) and a validated high-performance liquid chromatography with UV detection method for efavirenz (PPD, Richmond, VA). The assays for posaconazole, ATV, ritonavir, and efavirenz had lower limits of quantitation of 5.00, 1.00, 10.0, and 100 ng/mL, respectively; calibration range of 5.0-5000, 1.00-1000, 10.0-2000, and 100-10,000 ng/mL, respectively; precision [coefficient of variation (CV)] of 4.3%-7.9%, 6.67%-8.47%, 4.04%-14.4%, and 1.19%-1.96%, respectively; and accuracy (mean percent difference) of −3.3 to 5.8, −3.20 to 4.33, −2.67 to 7.86, and 0.0727-2.12, respectively.
Oral posaconazole was administered after subjects had consumed standardized high-fat meals, which is consistent with the conditions under which the absorption, elimination, and metabolism of oral 14C posaconazole were analyzed.14 ATV was administered with standard meals, and ritonavir and efavirenz were administered before meals.
Healthy subjects between the ages of 18 and 55 years, of either sex, of any race, and with a body mass index of 19-33 kg/m2 were eligible for enrollment in both study parts. Other inclusion criteria included results of clinical laboratory tests (complete blood count, blood chemistries, and urinalysis), physical examination, and electrocardiograms (ECGs) that were within normal limits or clinically acceptable to the investigator/sponsor; negative screens for drugs with high potential for abuse; no clinically significant disease that would interfere with the study evaluations; and the ability to adhere to restrictions and examination schedules.
Women were required to be nonlactating, to have a negative pregnancy test at screening, and to be of non-childbearing potential (ie, sterilized via hysterectomy or bilateral tubal ligation or at least 1 year postmenopausal) or, if of childbearing potential, practicing effective double-barrier contraceptive methods from at least 2 weeks before study start until 30 days after study completion. Men were required to practice double-barrier contraception from study start until 30 days after the last dose of study medication. Exclusion criteria included a history of any clinically significant local or systemic infectious disease within 4 weeks before drug administration; use of prescription or over-the-counter drugs [including oral contraceptives and excluding acetaminophen (paracetamol)] within 14 days before the study; use of alcohol- or xanthine-containing substances within 72 hours before study drug administration; use of any investigational drugs within 30 days before study drug administration; and blood donation within 90 days before study drug administration. Subjects could not be former narcotics addicts or alcoholics; have clinically significant allergy/intolerance to any compound in this study; be positive for hepatitis B surface antigen, hepatitis C antibodies, or HIV antibodies; have previously used posaconazole; currently smoke 10 or more cigarettes (or use other tobacco equivalent products) a day; or be members of or had family members at the research unit.
The clinical study protocol and written informed consent form were reviewed and approved by Ethikkommission beider Basel before the study began. Written informed consent was obtained from all subjects before any study-related activities, using a study-specific informed consent form.
In part 1, the primary comparison of interest was the contrast between the maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) values for ATV (alone and with ritonavir) administered with and without posaconazole at 7-day intervals. In part 2, the primary comparison of interest was the contrast between the Cmax and AUC values for efavirenz administered alone and with posaconazole at 10-day intervals. Summary statistics (means, SDs, and CV) for the concentration data at each sampling time were calculated. Log-transformed AUC and Cmax values were analyzed using a 1-way analysis of variance model with 90% confidence intervals to assess the effect of treatment on the pharmacokinetics of each compound. Other pharmacokinetic parameters determined were time to Cmax (Tmax), apparent volume of distribution (Vd/F), apparent total body clearance (CL/F), and terminal phase half-life (t½) based on plasma concentration for ATV, ritonavir, and efavirenz. Pharmacokinetic parameters assessed for posaconazole in part 1 were mean and median plasma concentrations on days 15, 16, 17, 57, 58, and 59 and in part 2 were AUC, Cmax, CL/F, and Tmax. Pharmacokinetic parameters were calculated using WinNonLin software (version 4.0.1 from Pharsight; St. Louis, MO). AUC was calculated using trapezoidal rule, whereas Vd/F was calculated as:
Equation (Uncited)Image Tools
where Kel is the terminal phase elimination rate constant.
Adverse events (AEs), blood for clinical laboratory tests, vital sign measurements, and ECGs were collected throughout the study to assess safety and tolerability. AEs were tabulated by body system/organ class and severity and were summarized by treatment and for the overall study. Severity of AEs was graded as mild, moderate, severe, or life threatening using the National Cancer Institute's Common Terminology Criteria for Adverse Events. The investigator assessed the relationship of any AE to use of the study drug using a scale of 0 (unlikely related), 1 (possibly related), or 2 (probably related).
Sample Size Determination
This was a descriptive study that was based on empirical rather than statistical considerations. Assuming an intersubject CV of 30% and power of 80%, with 12 subjects per comparison (usually a fixed sequence comparison), differences of approximately 22% were detected.
Twelve healthy adult subjects (11 men and 1 woman) between the ages of 27 and 54 years (mean age 45.1 years) were enrolled from January 18, 2006, to December 5, 2006, and all completed the study (Table 1). All subjects were white.
Seventeen healthy adult subjects (16 men and 1 woman) between the ages of 22 and 54 years (mean age 43.4 years) were enrolled from January 18, 2006, to December 5, 2006, and 10 (59%) completed the study (Table 1). All subjects were white.
A summary of mean ATV pharmacokinetic parameters is shown in Table 2. Based on log-transformed data, coadministration of oral posaconazole 400 mg twice daily for 7 days increased ATV Cmax and AUC by 2.6-fold and 3.7-fold, respectively, compared with when ATV was administered alone (Table 3). Also for ATV, absorption (Tmax) was delayed, mean t½ was increased, and clearance was decreased when the agent was coadministered with posaconazole (Table 2). Additional changes in ATV pharmacokinetics occurred when ATV was coadministered with posaconazole and ritonavir compared with when coadministered with ritonavir only: ATV Cmax and AUC increased by 1.5-fold and 2.5-fold, respectively, and median Tmax was delayed (Table 2). The mean plasma concentration-time profile for ATV is shown in Figure 1.
Based on log-transformed data, ritonavir Cmax and AUC increased by 1.5-fold and 1.8-fold, respectively, when ritonavir was coadministered with posaconazole and ATV compared with when coadministered with ATV only (Table 3). In addition, ritonavir absorption (Tmax) was delayed and mean t½ was prolonged from 4.3 to 5.5 hours (Table 2). The mean plasma concentration-time profile for ritonavir is shown in Figure 2. Posaconazole plasma concentrations were comparable for both dosing regimens (Table 4).
Based on log-transformed data, coadministration of posaconazole 400 mg twice daily for 10 days did not affect efavirenz exposure and only slightly increased efavirenz Cmax (Table 3). The pharmacokinetic profile for efavirenz alone was comparable to that when efavirenz was coadministered with posaconazole, with the exception of efavirenz absorption (Tmax) that was delayed from 2 to 4 hours (Table 2). However, coadministration of efavirenz 400 mg once daily for 10 days affected posaconazole pharmacokinetic parameters: Coadministration with efavirenz decreased posaconazole Cmax and AUC by 45% and 50%, respectively (Table 3). The mean plasma concentration-time profile for efavirenz is shown in Figure 3.
A total of 11 of 12 subjects (92%) reported at least 1 AE during the study. The most common AEs were ocular icterus (92%), pollakiuria (50%), abdominal pain (25%), herpes simplex infection (17%), and anorexia (17%). All AEs across all treatment groups were mild to moderate in severity, and no deaths or serious AEs occurred. No clinically significant changes occurred in hematologic parameters, vital signs, or ECGs. Clinically significant increases in total bilirubin occurred in 11 subjects: 6 subjects in arm 1 who received ATV/ritonavir and posaconazole (range, 79-156 μmol/L) and 5 subjects in arm 2 who received ATV and posaconazole (range, 48-121 μmol/L). The increase in total bilirubin was the only clinically important change in safety assessments that occurred across dosing regimens. However, an increase in unconjugated bilirubin would be expected in patients after ATV administration and is usually considered benign.
A total of 16 of 17 subjects (94%) reported at least 1 AE during the study. The most common AEs were dizziness (47%), fatigue (41%), headache (41%), somnolence (24%), and dry lips (24%). The majority of AEs were mild to moderate in severity, and no deaths or serious AEs occurred. No clinically significant changes occurred in hematologic parameters, blood chemistry, vital signs, or ECGs. Although there were no clinically important changes in safety assessments, 5 subjects discontinued participation in the study because of AEs (Table 5). An additional 2 subjects did not complete the study because of protocol noncompliance.
We conducted this study to assess interactions between posaconazole and the antiretrovirals ATV, ritonavir, and efavirenz. ATV, a CYP3A4 substrate, was first administered alone, to determine its steady state pharmacokinetic parameters, and then coadministered with ritonavir or posaconazole, both of which are CYP3A4 inhibitors, to determine the effect of each on ATV pharmacokinetics. Additionally, ATV was coadministered with ritonavir and posaconazole to determine if dual inhibition of ATV metabolism would further increase its plasma concentration. Because posaconazole and ritonavir are effective CYP3A4 inhibitors, no additional increases in ATV plasma concentrations were anticipated with the triple dosing regimen. As expected, coadministration of oral posaconazole 400 mg twice daily for 7 days increased ATV Cmax and AUC by 2.6-fold and 3.7-fold, respectively, compared with when ATV was administered alone. Also as expected, smaller increases in ATV and ritonavir plasma concentrations and exposure were observed after the triple dosing regimens. When ATV was administered with ritonavir, concomitant administration of posaconazole increased ATV Cmax and AUC by 1.5-fold and 2.5-fold, respectively, compared with ATV and ritonavir administration alone. Likewise, although not a study objective, coadministration with posaconazole increased Cmax and AUC of ritonavir when administered with ATV by 1.5-fold and 1.8-fold, respectively, compared with ritonavir and ATV administration alone. The potential inhibition of UGT1A1 by ATV,15 and possibly additional inhibition of CYP3A4 by posaconazole could in part contribute to an increase in plasma levels of ritonavir.
Previous studies of coadministration of ritonavir and other azoles have shown varying degrees of interactions. Concomitant administration with ketoconazole increased ritonavir AUC by 20% and increased ketoconazole AUC by 3.3-fold,22 whereas coadministration of fluconazole and ritonavir increased ritonavir Cmax and AUC by 15% and 12%, respectively.23 However, the latter interaction was not considered clinically significant, and no dosage adjustments are recommended for either drug when the 2 are coadministered.23 A study showed that ritonavir reduced the Cmax and AUC of voriconazole, although voriconazole slightly reduced the exposure of ritonavir, when the protease inhibitor was administered at a low dose (100 mg twice daily), and had no effect on ritonavir at a higher ritonavir dose (400 mg twice daily).24 Of note, some subjects experienced an increase in voriconazole exposure with coadministration, which is thought to result from CYP2C19 genetic polymorphism because voriconazole, in addition to being a CYP3A4 substrate, is metabolized by CYP2C19.24,25 Posaconazole plasma concentrations were similar when coadministered with either ATV or ATV and ritonavir.
The effect of posaconazole on efavirenz pharmacokinetics was also evaluated in this study. Efavirenz, an inducer and inhibitor of CYP3A4, was administered for 10 days to allow for full CYP3A4 induction and to allow the drug to reach steady state. Thereafter, posaconazole was coadministered for 10 additional days, so that it too could reach steady state concentrations. Coadministration of posaconazole 400 mg twice daily for 10 days did not affect efavirenz exposure. However, coadministration of efavirenz 400 mg once daily for 10 days decreased posaconazole Cmax and AUC by approximately 45% and 50%, respectively. The interaction between posaconazole and efavirenz is likely the result of induction of UGT by efavirenz. Posaconazole phase 2 glucuronidation is mediated by UGT1A4,13 and posaconazole exposure is decreased when coadministered with phenytoin26 or rifabutin,27 both of which are known inducers of UGT activity.28-30 Previous studies have shown that efavirenz also induces UGT activity.18-20
Decreases in plasma concentrations of other azole antifungals when coadministered with efavirenz have also been reported. In a study in HIV-infected patients, pretreatment with efavirenz decreased the Cmax and AUC of ketoconazole by 44% and 72%, respectively.31 In healthy volunteers, coadministration of voriconazole and efavirenz was found to decrease Cmax and AUC of voriconazole by 61% and 77%, respectively, and increase Cmax and AUC of efavirenz by 38% and 44%, respectively.25 Therefore, coadministration of standard doses of voriconazole and efavirenz is contraindicated.25 In a patient with AIDS-related disseminated histoplasmosis, coadministration of itraconazole and efavirenz resulted in persistently elevated urinary Histoplasma antigen levels and subtherapeutic plasma itraconazole concentrations (<0.05 μg/mL), necessitating a change in treatment of efavirenz to a protease inhibitor.32 Although a transporter such as p-glycoprotein may also contribute to an interaction, no data are currently available to support an involvement of the transporter.
Although this study was not designed to study the effect of ritonavir on posaconazole, the posaconazole mean Cmin data at the steady state in this study for the ATV and posaconazole arm (3090 ng/mL) are similar to the historical data from the same clinically recommended dose of posaconazole in healthy subjects (mean Cmin of 3260 ng/mL).33 Moreover, posaconazole mean Cmin data in this study, when ritonavir is added to ATV and posaconazole (2900 ng/mL), are similar to those from the ATV and posaconazole arm (3090 ng/mL). These data suggest that ATV and ritonavir are not affecting posaconazole exposure.
Coadministration of posaconazole with any of the antiretrovirals was generally safe and well tolerated. No clinically significant effects or changes across treatment groups were observed in the safety assessments of coadministration of posaconazole and ATV and/or ritonavir except for the increase in total bilirubin, which has been associated with high levels of ATV.34 Although 5 subjects who were administered posaconazole or posaconazole and/or efavirenz discontinued participation in the study because of AEs, none of them were considered to be clinically meaningful. It is important to note that the doses of ATV and efavirenz used in the studies were lower than doses used clinically.
Because HIV protease inhibitors and NNRTIs are CYP3A4 substrates, increased plasma concentrations of antiviral agents from these classes should be anticipated when coadministered with posaconazole. Thus, frequent monitoring of AEs and toxicity related to antiviral exposure is recommended in the event of coadministration of posaconazole and protease inhibitor or NNRTI antiviral. In addition, because of decreased posaconazole exposure, coadministration with efavirenz should be avoided unless the benefit to the patient outweighs the risk.
The authors would like to thank Meryl Mandle (ApotheCom, Yardley, PA) for her editorial assistance.
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