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PHARMACOKINETICS |
From Tibotec, Inc, Yardley, Pennsylvania (Dr Sekar, Dr Lefebvre), and Tibotec BVBA, Mechelen, Belgium (D. Kestens, Dr Spinosa-Guzman, Dr De Pauw, E. De Paepe, T. Vangeneugden, Dr Hoetelmans).
Address for reprints: Richard M. W. Hoetelmans, PharmD, PhD, Tibotec BVBA, Generaal De Wittelaan L11 B3, 2800 Mechelen, Belgium; e-mail: rhoetelm{at}tibbe.jnj.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: HIV • protease inhibitors • pharmacokinetics • darunavir • Prezista • food
Darunavir binds strongly to the HIV protease and is highly active against both wild-type and resistant strains of HIV.2,3 The clinical efficacy of darunavir/rtv has been demonstrated in 2 phase IIb studies, POWER 1 and 2 (TMC114-C213 and TMC114-C202). These randomized, controlled trials investigated the efficacy and safety of darunavir/rtv in treatment-experienced patients. Results at week 24 demonstrated that darunavir/rtv significantly improved virologic and immunologic outcomes compared with investigator-selected PIs and was generally well tolerated.4–7
Darunavir/rtv is intended to be given twice daily by oral administration to patients with HIV infection. It is therefore important to determine whether food intake would affect absorption of the drug. A study conducted early in drug development in healthy volunteers showed that intake with food increases the bioavailability of darunavir.8 The current study was conducted to determine the bioavailability and short-term safety and tolerability of a single-dose darunavir 400-mg tablet with low-dose ritonavir, under fasted and various fed conditions.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Healthy male and postmenopausal (or surgically sterile) female subjects aged 18 to 55 years were included in the study. Subjects were selected on the basis of a pretrial physical examination, medical history, electrocardiogram, vital signs, blood biochemistry, hematology, coagulation tests, urinalysis, and a negative drug screen. The study protocol was reviewed and approved by the IEC: Ethisch Comité (Universitair Ziekenhuis Antwerpen, Wilrijk, Belgium) and was conducted in accordance with the Declaration of Helsinki and the principles of good clinical practice. Written informed consent was obtained from all volunteers.
Study Treatments
During each session, all volunteers received ritonavir 100-mg capsules orally, twice daily, from days 1 to 5. On day 3, volunteers also received 1 darunavir 400-mg tablet within 5 minutes of ritonavir intake. Darunavir was taken either immediately after a standard breakfast (treatment A: 4 slices of bread, 1 slice of ham, 1 slice of cheese, butter, jelly, and 2 cups of coffee/tea with milk and/or sugar; 533 kcal, 21 g fat, 67 g carbohydrate, 19 g protein), under fasted conditions for at least 10 hours (treatment B), after a high-fat breakfast (treatment C: 2 eggs fried in butter, 2 strips of bacon, 2 slices of white bread with butter, 1 croissant with 1 slice of cheese, and 240 mL of whole milk; 928 kcal, 56 g fat, 65 g carbohydrate, 41 g protein), after a nutritional drink rich in proteins (treatment D: Ensure 250 mL chocolate or vanilla; 250 kcal, 8.4 g fat, 33.4 g carbohydrate, 10.5 g protein), or after a croissant with coffee (treatment E: 240 kcal, 12 g fat, 28 g carbohydrate, 5 g protein).
Pharmacokinetic and Safety Assessments
In each session, full pharmacokinetic profiles of both darunavir and ritonavir were assessed on day 3. Blood samples for analysis were taken predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 48, and 72 hours following drug administration. Full pharmacokinetic profiles of darunavir were determined up to 72 hours postadministration and for 1 dosing interval of ritonavir (12 hours). Ritonavir dosing was conducted on days 1 to 5 to maintain the enzyme-inhibiting effect of low-dose ritonavir throughout the pharmacokinetic sampling time of 72 hours postdosing of darunavir. Darunavir and ritonavir plasma concentrations were determined using a validated liquid chromatography mass spectrometry/mass spectrometry (LC/MS/MS) method. The internal standards were deuterated (d6)-ritonavir and (d4)-darunavir for ritonavir and darunavir, respectively. The mass transition was from 721.3 to 296.0 for ritonavir and from 548.2 to 392.0 for darunavir, respectively. The precision and accuracy for the darunavir and ritonavir quality control (QC) samples in plasma were less than 12% and met the predefined criteria of less than 20% for the low QC and 15% for the medium and high QC samples. The lower limit of quantification was 10.0 and 5.0 ng/mL for darunavir and ritonavir, respectively.9
Safety and tolerability were also assessed. Adverse events (AEs) were checked at every visit, and routine laboratory tests were conducted at screening; on day 1 (predose), day 3 (predose), and day 6; at discontinuation (if relevant); and on follow-up at weeks 1 and 4/5. Adverse events were graded according to the enhanced AIDS Clinical Trials Group (ACTG) grading scale, and laboratory tests were evaluated using the Division of AIDS (DAIDS) toxicity grading scale. For laboratory tests in which toxicities were not defined by this list, the abnormality (above or below normal range) was used.
Pharmacokinetic and Statistical Analysis
Descriptive statistics were calculated for the plasma concentrations of darunavir and ritonavir and pharmacokinetic parameters by noncompartmental methods using WinNonlin Professional (version 4.1; Pharsight Corporation, Mountain View, Calif). The pharmacokinetic parameters calculated for darunavir and/or ritonavir were as follows: predose plasma concentration (C0h), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), time to reach the maximum plasma concentration (tmax), terminal elimination half-life (t1/2,ß), area under the plasma concentration-time curve (AUC) from time of administration up to 12 hours after dosing (AUC12), and AUC from time of administration up to the last time point with a measurable concentration postdose (AUClast). AUC12 and AUClast were both calculated by linear trapezoidal summation. The terminal half-life was calculated as ln2/
z, where z represents the elimination rate constant determined by linear regression of the terminal points of the ln-linear plasma concentration-time curve. Cmax and tmax were determined by visual inspection of the concentration-time profiles of darunavir.
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The primary pharmacokinetic parameters of interest for darunavir were Cmax and AUClast on the logarithmic scale. The least square (LS) means of the primary parameters of darunavir were estimated using linear mixed-effect modeling, controlling for treatment, sequence, and period as fixed effects and subject as a random effect. The ratio of LS means of test and reference values was calculated for each treatment, and 90% confidence intervals (CIs) were constructed. Both the ratios of LS means and the 90% CIs were retransformed to the original scale. Treatment and period effects were considered significant at the 5% level, and sequence effects were considered significant at the 10% level. The crossover design tool of WinNonlin Professional (Pharsight Corporation) was used to perform a nonparametric Koch analysis on darunavir tmax.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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All volunteers were of Caucasian origin. In panel 1, the median age was 32 years (range, 22-50) with a median body mass index (BMI) of 24.9 kg/m2 (range, 20-29). In panel 2, the median age was 49 years (range, 34-55) with a median BMI of 23.1 kg/m2 (range, 19-27). Six subjects in panel 1 and 10 subjects in panel 2 were nonsmokers.
Darunavir Pharmacokinetics
The profile of mean darunavir plasma concentration versus time following the study treatments is shown in Figure 1. The mean darunavir plasma concentration-time profiles were comparable for all administrations under fed conditions (treatments A, C, D, and E). Compared with these treatments, administration of darunavir under fasted conditions (treatment B) resulted in a lower mean darunavir plasma concentration-time profile. Maximum plasma concentrations were reached approximately 1.5 hours postdose in the fasted state. This was increased to 3 to 4 hours postdose for all fed conditions.
Each meal type was compared with the reference treatment (treatment A, standard breakfast), and the ratios of the LS means of Cmax and AUClast were close to 100% in all cases, except for the comparison between treatment A and treatment B (fasted state) (Table I). In this case, systemic exposure to darunavir (AUClast) was reduced by approximately 30% after administration under fasted conditions (treatment B) as compared with administration after a standard breakfast (treatment A). Interindividual variability on darunavir pharmacokinetics was similar between treatment groups and ranged from 18% to 35% for Cmax and AUClast.
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Ritonavir Pharmacokinetics
Mean plasma concentration-time curve profiles of ritonavir on day 3 following the different study treatments are shown in Figure 3. There were no differences in predose plasma concentrations of ritonavir on day 3 compared with those on days 4 and 5 of each treatment, suggesting that steady state had been achieved by day 3 for low-dose ritonavir.
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Safety and Tolerability
The combination of darunavir as a single-dose 400-mg tablet, with ritonavir 100 mg twice daily for 5 days, was generally well tolerated. Overall, 20 volunteers (83%) reported at least 1 AE during the study period; all AEs were grade 1 or 2 in severity. The most common AE was headache, which was reported by 10 volunteers (42%). Other AEs reported by more than 1 individual included diarrhea, vomiting, and pruritus (in 21%, 8%, and 13% of volunteers, respectively). One serious AE was reported during follow-up (grade 2 back pain due to discal herniation, requiring hospitalization), which was not considered to be related to study medication.
Within the clinical laboratory tests, there were no treatment-emergent grade 3 or 4 abnormalities. Four volunteers developed a grade 2 increase in total cholesterol (maximum changes from 0.3-0.8 mmol/L); these volunteers already had grade 1 elevations in total cholesterol at baseline. All other treatment-emergent graded laboratory abnormalities were grade 1 in severity. No consistent or clinically relevant changes over time in median laboratory parameters were observed.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Consistent with our findings for darunavir, ingestion with food is known to increase the bioavailability of several PIs: the AUCs of saquinavir, nelfinavir, lopinavir/r, and atazanavir are increased by 700%, 200% to 300%, 48% to 97%, and 35%, respectively,10 when compared with the fasted state. This increase in bioavailability may be partly attributed to higher drug solubility in the presence of food.
This study was conducted in healthy volunteers. Although exposure to darunavir is higher in HIV-infected patients compared to that in healthy volunteers, this is primarily due to the difference in the levels of alpha-1 acid glycoprotein (AAG), the protein that darunavir primarily binds to. In all clinical trials in HIV-infected patients, darunavir has always been administered with food. Therefore, the results of this study can be extrapolated to the target population of HIV-infected patients.
In summary, darunavir exposure following administration of the 400-mg tablet formulation is increased by approximately 30% in the fed condition, compared with the fasted condition, and is comparable for different types of meals. It is recommended that darunavir/rtv be given with food, but there are no restrictions on the type of food consumed as this does not affect exposure to darunavir.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: All authors are salaried employees of Tibotec.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Prezista (darunavir) [prescribing information]. Yardley, Pa: Tibotec, Inc; 2006.
2. De Meyer S, Azijn H, Surleraux D, et al. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother. 2005;49: 2314-2321.
3. King NM, Prabu-Jeyabalan M, Nalivaika EA, Wigerinck P, de Bethune MP, Schiffer CA. Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. J Virol. 2004;78: 12012-12021.
4. Katlama C, Carvalho MTM, Cooper D, et al. TMC114/r outperforms investigator-selected PI(s) in 3-class-experienced patients: week 24 primary efficacy analysis of POWER 1 (TMC114-C213). Presented at: IAS; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract WeOaLB0.102.
5. Grinsztejn B, Arasteh K, Clotet B, et al. TMC114/r is well tolerated in 3-class-experienced patients: week 24 primary safety analysis of POWER 1 (TMC114-C213). Presented at: IAS; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract WePeLB6.201.
6. Wilkin T, Haubrich R, Steinhart CR, et al. TMC114/r superior to standard of care in 3-class-experienced patients: 24-wk primary analysis of the POWER 2 study (C202). Presented at: ICAAC; December 16-19, 2005; Washington, DC. Abstract 2860.
7. Berger D, Bellos N, Farthing C, et al. TMC114/r in 3-class-experienced patients: 24-wk primary safety analysis of the POWER 2 study (C202). Presented at: ICAAC; December 16-19, 2005; Washington, DC. Abstract H-1094.
8. Hoetelmans R, Lefebvre E, van der Sandt I, et al. Pharmacokinetics and effect of food on TMC114, a potent next generation protease inhibitor, boosted with low-dose ritonavir. Presented at: IWCPHIV; April 1-3, 2004; Rome, Italy. Abstract 5.6.
9. Bouche MP, Michielsen L, Piot M, Timmerman P. Swift and simultaneous determination of darunavir (TMC114) and ritonavir in human plasma using LC-MS/MS. Presented at: 17th International Mass Spectrometry Conference; August 27–September 1, 2006; Prague, Czech Republic. Abstract TuP-042.
10. Boffito M, Acosta E, Burger D, et al. Current status and future prospects of therapeutic drug monitoring and applied clinical pharmacology in antiretroviral therapy. Antivir Ther. 2005;10: 375-392.[Web of Science][Medline]
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