The pharmacokinetic (PK) profile of darunavir with low-dose ritonavir (DRV/r) in various multiple-dose regimens over 120 hours
Reported by Jules Levin
9th International Workshop on Clinical Pharmacology of HIV Therapy
April 7-9, 2008
Marta Boffito,1 Graeme Moyle,1 Andrew Hill,2,3 Vanitha Sekar,4 Eric Lefebvre,5 Martine De Pauw,3 Ralph DeMasi,4 Richard Hoetelmans3
1Pharmacokinetic Research Unit, St Stephen's Centre, Chelsea and Westminster Hospital, London, UK; 2Department of Pharmacology, University of Liverpool, Liverpool, UK;
3Tibotec BVBA, Mechelen, Belgium; 4Tibotec Inc., Yardley, PA, USA; 5Janssen-Cilag, Tilburg, The Netherlands
Following repeated DRV/r dosing of 800/100mg once-daily, DRV concentrations
remained above the EC50 value of 55ng/mL for at least 48 hours in all volunteers after the last administered DRV dose while ritonavir dosing was continued.
Once-daily DRV/r administered at a dose of 800/100mg
- allows for convenient, once-daily dosing
- can maintain adequate DRV plasma concentrations for prolonged periods of time
- is well tolerated.
These findings are consistent with recent clinical data on once-daily use of DRV/r 800/100mg in treatment-naive patients participating in the Phase III ARTEMIS trial.4
With its long half-life and suitable exposure following once-daily dosing, DRV is
expected to provide benefits in HIV-1-infected patients, and may support the
long-term sustainability of combination ARV therapy.
· Once-daily protease inhibitor (PI) dosing offers the advantages of a reduced pill burden, a less complicated treatment regimen and improved convenience (which may improve adherence), compared with twice-daily PI dosing. In addition, the daily dose of ritonavir needed may be halved for some PIs.
· DRV/r at a dose of 600/100mg bid has been approved in the USA,1 Europe2 and other countries for the treatment of HIV-1 infection in treatment-experienced adults.
· Coadministration of DRV with ritonavir decreases DRV clearance, increasing the DRV terminal elimination half-life (t1/2term) to approximately 15 hours.3
· Once-daily DRV/r may thus present an appropriate therapeutic strategy. DRV/r 800/100mg qd has been evaluated in patients with a broad range of treatment experience, including
- treatment-naive patients in the Phase III ARTEMIS trial4
- antiretroviral (ARV)-experienced patients in the POWER 1 and 2 trials.5,6
· In this study (TMC114-C137), we compared the steady-state plasma pharmacokinetics of DRV for various doses of DRV/r given once or twice daily in
TMC114-C137 was a Phase I, open-label, parallel-group, dose-ranging study with the primary objective of determining the plasma pharmacokinetics of various oral DRV/r treatment regimens.
Secondary objectives were to assess
- dose-proportionality of DRV exposure for the investigated treatment regimens
- percentage of unchanged DRV excreted in urine
- safety and tolerability of the investigated treatment regimens.
The study population consisted of 40 HIV-negative volunteers grouped into five
panels, each composed of eight healthy adults. During five parallel sessions, volunteers were treated from Day 1 to 7 with the following DRV/r treatment regimens: A) 400/100mg qd; B) 800/100mg qd; C) 1200/100mg qd; D) 400/100mg bid and E) 800/100mg bid (Figure 1). Administration of ritonavir continued until Day 11 of each session.
On Days 1 and 7 of each treatment, DRV and ritonavir were coadministered after a standard breakfast.
On Day 7 of each session, the complete urinary output during the intervals 0-12 hours and 12-24 hours (for Treatments A, B and C) or during the interval 0-12 hours (for Treatments D and E) after the morning intake of Day 7 was collected.
DRV and ritonavir plasma concentrations and DRV urine concentrations were determined using validated liquid chromatography tandem mass spectrometry methods
- lower limit of quantification in plasma was 10ng/mL for DRV and 5ng/mL for ritonavir
- lower limit of quantification in urine was 20ng/mL for DRV.
Steady-state plasma PK profiles of DRV were determined up to 120 hours postdose on Day 7 to evaluate the time taken for DRV concentrations to fall below the prespecified threshold of 55ng/mL, based on the protein-binding corrected in-vitro EC50 value for wild-type HIV-1 protease.7
PK analyses were performed as follows
- WinNonlin ProfessionalTM (version 3.3; Pharsight Corporation, Mountain View,
California, USA) software was used to compare Treatment A versus B, A versus C, B versus C and D versus E for DRV
- primary PK parameters included the predose plasma concentration (C0h), dose-normalized minimum plasma concentration between 0 hour and the dosing interval (Cmin), the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve on the logarithmic scale calculated up to 12 hours postdose (AUC12h) for twice-daily regimens and up to 24-hours postdose (AUC24h) for once-daily regimens
- time to Cmax and t1/2term were also assessed, as well as urine parameters on Day 7, including the percentage of the dose excreted in the urine 0-12 hours postdose (Durine,0-12h), Durine,12-24h (for once-daily dosing) and Durine,total
- the least square means (LSM) of the primary parameters for each treatment group was estimated with a linear, mixed-effects model, controlling for dose as a fixed effect
- a 90% confidence interval (CI) was constructed around the difference between the LSM of test and reference, and both the difference between the LSM and the 90% CI limits were retransformed to the original scale.
Safety and tolerability evaluations were recorded throughout the study, including a 4-week follow-up period after ritonavir administration.
A total of 40 volunteers, 34 (85%) of whom were male, participated in the trial; 39 were Caucasian and one was African-American. The median ages in the five panels ranged from 35 to 44 years.
All volunteers had negative HIV serology, negative hepatitis B surface antigen and negative hepatitis B core antibody IgM.
Data were excluded from the PK descriptive statistics and statistical analyses for
- one volunteer in the Treatment B group who received disallowed comedications for this study
- one volunteer in the Treatment C group who tested positive for hepatitis C antibody.
DRV PK parameters
On Day 7, Cmax values for DRV were reached between 2.5 and 4 hours postdose for all treatments.
Table 1 shows the PK parameters for DRV at Day 7
- mean concentrations of DRV after Treatment B and Treatment C were comparable
- mean C0h for all treatments exceeded the protein-binding corrected in-vitro EC50 value of 55ng/mL.7
Following intake of DRV 800/100mg qd (Treatment B), DRV concentrations remained above the EC50 value of 55ng/mL for at least 48 hours in all volunteers after the last administered dose (Figure 2 and Table 2).
Based on the ratio of LSM and associated 90% CIs of the dose-normalized parameters at Day 7 (Table 3)
- AUC24h and Cmin of DRV increased in proportion with dose for the once-daily regimens
- a less than dose-proportional increase in Cmax was noted for the once-daily regimens (between Treatment A and B, and between Treatment A and C)
- a dose-proportional increase in Cmin and less than dose-proportional increases in Cmax and AUC12h were observed for the twice-daily regimens.
The mean t1/2term of DRV ranged from 10.9 to 17.2 hours. No influence of ritonavir dose regimens on DRV t1/2term was observed.
The mean urinary excretion of DRV was similar for all treatments and was 3-5% of the dose administered within a dosing interval (Table 4).
Ritonavir PK parameters
On Day 7, Cmax values for ritonavir were reached between 4 and 6 hours postdose for all treatments.
Daily ritonavir exposure for the twice-daily regimens was approximately twice that observed for the once-daily regimens (Table 5). At Day 7, mean AUC24h for ritonavir was comparable for the once-daily regimens.
Safety and tolerability
Overall, 27 of the 40 volunteers (67.5%) reported at least one adverse event (AE) during the study. During the treatment phase of the study
- the majority of AEs (31/34 [91%]) were grade 1 or 2 in severity
- there was no dose-response relationship for the incidence of AEs or laboratory abnormalities with the DRV/r treatment regimens.
All changes in laboratory evaluations were grade 1 and grade 2, with the exception of
- treatment-emergent grade 2 and 3 increases in cholesterol reported during DRV/r administration in 7/40 (18%) and 1/40 (3%) volunteers, respectively
- a grade 3 increase in lipase levels at Day 7 following completion of DRV/r administration, considered possibly related to study drug, in one volunteer in the Treatment A group; the volunteer had grade 1 lipase levels at screening and discontinued on Day 12.
No serious AEs or grade 4 laboratory abnormalities in any parameter were observed during the study.
1. Tibotec Inc. PREZISTA (darunavir) Prescribing Information. February 2008 [accessed 10 March 2008]. Available from: http://www.prezista.com/prezista/.
2. PREZISTA (darunavir) Summary of Product Characteristics. February 2007 [accessed 10 March 2008].
Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/prezista/H-707-PI-en.pdf.
3. Hoetelmans R, et al. 10th Conference on Retroviruses and Opportunistic Infections, Boston, USA, 10-14 February 2003. Abstract 549.
4. DeJesus E, et al. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA,
17-20 September 2007. Abstract H-718b.
5. Katlama C, et al. AIDS 2007;21:395-02.
6. Haubrich R, et al. AIDS 2007;21:F11-F18.
7. Sekar V, et al. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, 3-6 February 2008. Abstract L-103.