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Clinical pharmacology of TMC114 - a new HIV protease inhibitor
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Reported by Jules Levin
XVI IAC Toronto, Aug 2006
Sekar V,1 Spinosa-Guzman S,2 Lefebvre E,1 Hoetelmans R2
1Tibotec Inc., Yardley, PA, USA; 2Tibotec BVBA, Mechelen, Belgium
poster TUPE0083
This poster presents a summary of TMC114 pharmacokinetics that have been determined in preclinical and clinical studies.
Author Conclusions
- The bioavailability of TMC114 was substantially increased when co-administered with low-dose RTV 100mg bid. TMC114 should always be co-administered with RTV 100mg.
- Sufficient PK enhancement of TMC114 (in terms of target concentrations) was achieved with a co-administered RTV dose of 100mg. The use of a higher dose of RTV did not result in any relevant increase in TMC114 exposure.
- TMC114/r should be taken with food, but the type of meal does not affect exposure to TMC114.
- The mean plasma protein binding of TMC114 was 95%. TMC114 was mainly bound to AAG; this is consistent with almost all of the other commercially available HIV-1 PIs.
- In the presence of RTV, the metabolism of TMC114 was markedly reduced and almost exclusively catalyzed by CYP3A4.
- TMC114 pharmacokinetics increased less than proportional to dose in patients in the dose range of 400mg qd- 600mg bid.
- All patients receiving TMC114/r 600/100mg bid in the POWER studies achieved Cmin values above the predefined target for PI-resistant virus, supporting the selection of the TMC114/r 600/100mg bid dose for treatment-experienced HIV-1-infected patients.
ABSTRACT
Background: The protease inhibitor (PI) TMC114 (darunavir) is potent in vitro against wild-type and PI-resistant HIV. This analysis presents an overview of TMC114 pharmacokinetic (PK) properties.
Methods: Several Phase I studies conducted in HIV-negative volunteers determined the absorption, distribution, metabolism, excretion and elimination of TMC114 (400mg) with low-dose (100mg) ritonavir (RTV; TMC114/r). PK evaluations performed in treatment-experienced, HIV-infected patients established the effect of increasing TMC114 dose on the extent of drug exposure (area-under-the-curve [AUC]).
Results:
In HIV-negative volunteers, the absolute oral bioavailability of TMC114 alone increased from 37% to 82% when co-administered with RTV, indicating an almost complete inhibition of TMC114 first-pass elimination by RTV. PK enhancement with 100mg RTV increased systemic TMC114 exposure by approximately 14-fold. A higher RTV dose (200mg) increased RTV exposure
but did not significantly increase TMC114 exposure.
Although TMC114 exposure was approximately 30% lower under fasted than fed conditions, it was unaffected by meal type.
TMC114 was 95% plasma protein-bound, mostly with alpha-1-acid glycoprotein (AAG). Its metabolism was extensive and almost exclusively catalyzed by CYP3A4. A mass-balance study showed that TMC114 was excreted mainly in feces (80%) and to a lesser extent in urine (12%). The amount of unchanged
TMC114 increased from 7% when administered alone to 49% when co-administered with RTV. The terminal plasma elimination half-life of TMC114 was 15 hours in the presence of low-dose RTV. In treatment-experienced patients, TMC114 exposure increased less than proportionally with increasing doses, and plasma minimum trough concentration (Cmin) was above EC50 values (corrected for protein binding) for PI-resistant virus at the recommended TMC114/r 600/100mg bid dose.
Conclusions:
TMC114/r should be taken with food (any type). Co-administration of TMC114 with low-dose RTV increases its oral bioavailability and systemic exposure. All patients treated with TMC114/r 600/100mg bid achieved TMC114 plasma concentrations above the EC50 value for PI-resistant virus, supporting the dose selection in treatment-experienced patients.
Introduction
TMC114 is a novel PI that exhibits significant in-vitro antiviral activity against both wild-type and resistant HIV isolates, including multidrug-resistant strains.1
- Two Phase IIb, randomized, controlled trials investigated the efficacy and safety of TMC114/r in treatment-experienced patients (POWER 1 [TMC114-C213] and POWER 2 [TMC114-C202])
- in a 24-week pooled analysis of POWER 1 and 2 where all patients received an optimized background regimen (OBR), 45% of patients receiving the recommended TMC114/r 600/100mg bid dose achieved HIV-1 RNA <50 copies/mL versus 12% of patients receiving investigator-selected control PI(s). TMC114/r was generally well tolerated in these studies.
- POWER 3 is an integrated analysis of two non-randomized, open-label trials (TMC114-C215/C208), which were conducted to further define the effectiveness and safety of the TMC114/r 600/100mg bid dose for treatment-experienced patients.7
RESULTS
Impact of low-dose RTV on TMC114 bioavailability
- Plasma concentration-time profiles of TMC114 in response to oral and iv administration, with or without co-administration of RTV are shown in Figure 1.8 Systemic exposure of TMC114 was markedly increased in the presence of RTV.
Figure 1. Mean plasma concentration-time profiles of TMC114 after a single iv infusion of 150mg TMC114 (A), a single oral 600mg tablet of TMC114 (B), a single iv infusion of 150mg TMC114 plus oral RTV (C) and a single oral 600mg tablet of TMC114 plus oral RTV (D).
- Mean systemic clearance of TMC114 and TMC114/r was 32.8±7.0L/hour and 5.9±2.1L/hour, respectively.
- In the presence of low-dose RTV, the oral bioavailability of TMC114 was increased more than two-fold, from 37% to 82%, indicating that first-pass elimination of TMC114 was almost completely inhibited.
- Combined with five-fold inhibition of the systemic clearance of TMC114, the net result (the 'PK enhancing effect') was an approximately 14-fold increase in systemic exposure when TMC114 600mg was given orally in combination with RTV 100mg bid.
- The use of RTV 200mg qd increased exposure to RTV compared with RTV 100mg bid, but this occurred without concomitant increase in exposure to TMC114 (Table 1). However, exposure to TMC114 was generally comparable between the two dosing regimens of TMC114/r 600/200mg qd and 300/100mg bid, indicating that the desired PK enhancement of TMC114 was achieved with the co-administered RTV dose of 100mg.
Effect of food and meal type on TMC114 bioavailability
- Concentration-time profiles of TMC114 administered as a tablet formulation with different types of meal are shown in Figure 2.9
Figure 2. Mean plasma concentration-time profiles of single-dose TMC114 administered after one of four different meal types at breakfast, or under fasted conditions with RTV 100mg bid.
- The mean plasma concentration-time profiles of TMC114 were comparable for all administrations under fed conditions. However, administration under fasted conditions resulted in a lower mean TMC114 plasma concentration-time profile:
- systemic exposure to TMC114, co-administered with low-dose RTV, decreased by approximately 30% under fasted versus fed conditions.
Protein binding of TMC114
- The mean plasma protein binding of TMC114 was 95.3% at a TMC114 concentration of 500ng base-eq/mL in plasma (clinically relevant concentrations). The percentage protein binding was dependent on the plasma concentration of TMC114, including concentrations above 5,000ng/mL (Table 2).
- TMC114 was mainly bound to AAG, and to a lesser extent to albumin.
Table 2. Mean plasma protein binding at different concentrations of 14C-TMC114 in plasma of healthy males.
Metabolism, excretion and elimination of TMC114
- In an in-vitro metabolism study performed to characterize the CYP isozymes involved in the oxidative metabolism of TMC114, only ketoconazole (predominantly a CYP3A4 inhibitor) showed significant inhibition (55%) of TMC114 metabolism, and only CYP3A4 showed metabolic activity towards TMC114.
- In-vitro metabolism studies in human liver microsomes showed TMC114 to be metabolized to three primary TMC114 metabolites: M19 (by carbamate hydrolysis), M23 (by aliphatic hydroxylation) and M29 (by aromatic hydroxylation), and to three minor metabolites: M27, M28 (by alicyclic hydroxylation) and M6 (by a different pathway). TMC114 metabolism to these six metabolites was mainly catalyzed by CYP3A enzymes.
- At 168 hours after dose administration, an average of 81.7% and 79.5% of the administered 14C-TMC114-related radioactivity was recovered in feces and 12.2% and 13.9% in urine in the absence and presence of RTV, respectively
- after 48 hours of oral dosing, 14C-TMC114 was extensively metabolized in the absence of RTV, with only 7% of the dose excreted unchanged
- metabolism of 14C-TMC114 was markedly reduced in the presence of RTV, with 48.8% of the dose excreted unchanged in feces and urine
- therefore, the renal clearance of TMC114 is limited, and a decrease in total body clearance is not expected in patients with renal impairment.
- A dose-ranging study determined the terminal plasma elimination half-life of TMC114 to be 15 hours (range 12.7- 16.4 hours) in the presence of low-dose RTV.6
PK analyses of TMC114 in the POWER 1, 2 and 3 studies
- For POWER 1 and 2, TMC114 AUC increased less than dose proportionally (Table 3 and Figure 3); the 100% increase in TMC114 dose between the two qd groups resulted in an approximate 60% increase in AUC, and the 50% increase in TMC114 dose between the two bid groups resulted in an approximate 29% increase in AUC.
Figure 3. Median, 25% and 75% percentiles, minimum and maximum of AUC24h and C0h for TMC114 in the respective dosing regimens (integrated data from POWER 1 and 2, primary 24-week analysis).
- For each treatment group in POWER 1 and 2, the mean plasma TMC114 trough concentration exceeded the predefined target of 550ng/mL (based on the EC50 value for PI-resistant HIV-1 strains when corrected for protein binding). Furthermore, in POWER 1, 2 and 3 this target were also exceeded in all patients with sparse sampling data who were treated with TMC114/r 600/100mg bid.
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