Potential drug-drug interactions of telaprevir with amlodipine and atorvastatin were investigated in healthy volunteers by comparing the PK of these drugs with and without the coadministration of telaprevir. A formulation containing a combination of amlodipine and atorvastatin (Caduet) was used in this study for dosing convenience. No significant interaction between amlodipine and atorvastatin was expected.
A clinical drug-drug interaction study of telaprevir and midazolam showed that telaprevir increased the AUC of oral midazolam almost 9-fold (4
), indicating that telaprevir is a potent inhibitor of CYP3A4. Amlodipine is a dihydropyridine calcium antagonist drug and has been reported as a substrate and mild inhibitor of CYP3A from both in vitro
liver microsomal incubation and clinical studies (9
). Atorvastatin, one of the most commonly prescribed HMG-CoA reductase inhibitors, is also a substrate of CYP3A (6
). Adverse events such as rhabdomyolysis and myopathy have been reported with statins, and most of the statin drug interactions are attributed to metabolism catalyzed by cytochrome P450 (22
). Thus, clinically significant changes in the PK of amlodipine and atorvastatin, administered as Caduet, were anticipated with the coadministration of telaprevir.
Results from the present study indicate that telaprevir significantly inhibited the metabolism of both amlodipine and atorvastatin. The bioavailability of amlodipine has been reported to be ~60% (14
). It is extensively metabolized by the liver and is very slowly cleared from the body (elimination t1/2
, ~45 h). Its volume of distribution is known to be large (~21 liters/kg), with a high level of binding to the plasma albumin (~98%) (15
). When amlodipine was coadministered with telaprevir, its AUC0-∞
increased 2.79-fold and its Cmax
increased 1.27-fold. The mean (SD) t1/2
increased from 41.3 (8.2) h to 95.1 (23.6) h, and the mean (SD) apparent clearance (CL/F) decreased from 38.0 (11.8) liters/h to 12.3 (2.97) liters/h. The increased t1/2
associated with the clearance decrease signifies the inhibitory effect of telaprevir on the metabolism of amlodipine. An effect of a similar magnitude on amlodipine has been observed in other studies with antiviral agents that are CYP3A inhibitors. For example, combined dosing of indinavir and ritonavir increased the median amlodipine AUC0-24
by 90% (n
= 18) (5
The effect of telaprevir on atorvastatin disposition was more pronounced. Atorvastatin is given in the acid form, and its Cmax
is achieved quickly (~1 to 2 h postdose) (10
). Atorvastatin acid undergoes extensive first-pass metabolism in the gut and the liver, and therefore its oral bioavailability is only ~14%. Its volume of distribution has been reported to be ~380 liters, with a high degree of plasma protein binding, mainly to albumin (98%) (22
Upon the coadministration of telaprevir with a single dose of amlodipine-atorvastatin, the atorvastatin AUC0-∞
increased 7.88-fold and the atorvastatin Cmax
increased 10.6-fold. These results suggest that the primary effect of telaprevir on atorvastatin is to increase its bioavailability (F) by decreasing its first-pass metabolism by CYP3A and/or increasing its net absorption by inhibiting P-glycoprotein-mediated efflux back to the gut. The effect of telaprevir on the hepatic metabolism of atorvastatin does not appear to be significant in its overall disposition. An effect of a similar magnitude on atorvastatin has been observed in studies using some other CYP3A inhibitors. For example, the AUC and Cmax
of atorvastatin were increased about 9-fold when it was coadministered with tipranavir-ritonavir at steady state (16
With coadministration of telaprevir, the mean (SD) apparent clearance decreased from 685 (272) liters/h to 83.8 (32.7) liters/h and the apparent volume of distribution decreased from 8,984 (3,431) liters to 838 (405) liters. The mean (SD) terminal t1/2
decreased from 9.44 (2.64) h to 6.75 (1.55) h with the coadministration of telaprevir, although this difference was not statistically significant. Inhibition of atorvastatin metabolism would be expected to increase the atorvastatin t1/2
. This unexpected result may be caused by the inhibition of transporters involved in the hepatic uptake of atorvastatin, such as organic anion-transporting polypeptide 1B1 (OATP1B1), which could reduce the volume of distribution of atorvastatin to an extent similar to or greater than the observed decrease in systemic clearance. Such a mechanism has been hypothesized for the effect of cyclosporine (an inhibitor of OATP1B1) on rosuvastatin, a statin which is also a substrate of OATP1B1 and whose t1/2
was decreased by half upon the coadministration of cyclosporine (19
). Other statins that are substrates of OATP1B1, such as cerivastatin, fluvastatin, and atorvastatin, showed unaltered t1/2
s, while severalfold AUC and Cmax
increases resulted when the drugs were coadministered with cyclosporine (18
). However, at this time, the effect of telaprevir on OATP1B1 is unknown.
The mean AUC0-∞
-hydroxy atorvastatin decreased by approximately 70% after telaprevir coadministration; however, most concentrations of para
-hydroxy atorvastatin were below the LLOQ, making noncompartmental analysis for this metabolite not feasible. In the 2 volunteers in whom para
-hydroxy atorvastatin was measurable before (day 1) and after (day 17) the coadministration of telaprevir, the concentrations of this metabolite increased about 6-fold. On day 17, but not day 1, several other volunteers had measurable concentrations of para
-hydroxy atorvastatin. While these results were not anticipated, it has been reported that para
-hydroxy atorvastatin, but not ortho
-hydroxy atorvastatin, is also formed by CYP2C8 in addition to CYP3A (7
). Therefore, in the presence of greater systemic exposure of atorvastatin during the coadministration of telaprevir, it is plausible that more para
-hydroxy atorvastatin is formed via CYP2C8 and its concentration in plasma is increased.
The PK of telaprevir were evaluated after coadministration at steady state with a single dose of amlodipine-atorvastatin. The Cmax
were similar to the steady-state estimates obtained in other studies (21
). This suggests that adequate telaprevir exposure was achieved in this study and a clinically significant effect of amlodipine or atorvastatin on telaprevir is unlikely.
The coadministration of multiple doses of telaprevir with one dose of amlodipine and atorvastatin administered in 2 periods was well tolerated. There were no serious, life-threatening, or severe adverse events, no volunteers discontinued due to an adverse event, and most of the adverse events reported were mild. The frequently reported adverse events included, headache, dizziness, diarrhea, and nausea, all of which have been reported in other clinical trials after the administration of telaprevir alone (8
). The low frequency and/or lack of adverse events commonly associated with amlodipine and atorvastatin may be attributed to the single-dose regimen of these drugs used in this study.
In summary, the results of this study suggest that telaprevir significantly increased exposure to amlodipine and atorvastatin (Cmax
). Atorvastatin coadministration with telaprevir is contraindicated. When amlodipine is coadministered with telaprevir, caution should be used and an amlodipine dose reduction should be considered. Clinical monitoring is recommended. Please check the INCIVEK package insert for full information and/or updates (3