Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents - A potentially lethal cocktail
(see article below editorial)
Editorial
Download the PDF here
"Finally, telaprevir has not been studied in pre-, post-, or peritransplant patients. The degree of the interaction with calcineurin inhibitors reported here suggests potential implications for patient safety. Telaprevir should not be administered to these patients, because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained."
HEPATOLOGY, July 2011
Michael Charlton, MD, FRCP, Department of Gastroenterology and Hepatology, Mayo Clinic Transplant Center CH-10, Mayo Clinic, 200 First St. S.W., Rochester, MN. 55905. E-mail: charlton.michael@ mayo.edu; Fax: 507-266-1856.
Hepatitis C virus (HCV) associated liver disease continues to be the most common indication for liver transplantation. Although the impact of HCV infection varies substantially between recipients, allograft failure secondary to recurrence of HCV infection is the most frequent cause of death and graft failure in HCV-infected recipients, accounting for two thirds of long term graft loss.1 Histological features of hepatitis develop in approximately 75% of recipients in the first 6 months following liver transplantation,2 with up to 30% progressing to cirrhosis by the fifth postoperative year.2 Mortality and graft loss related to recurrence of HCV has led to long-term graft survival for recipients with HCV infection that is lower than that of recipients undergoing liver transplantation for most other indications.3 Patients who achieve sustained virological response (SVR) to treatment of posttransplant HCV infection experience less severe recurrence and lower mortality and graft loss rates than nonresponders.4-6 Although the likelihood of response to antiviral therapy varies substantially with donor and recipient IL28B genotype,7 the overall safety and efficacy of peginterferon and ribavirin in the treatment of posttransplant HCV infection are both lower than we would wish.8, 9 A recent prospective randomized controlled trial found that less than 60% of liver transplant recipients are able to complete peginterferon and ribavirin antiviral therapy and, on an intention to treat basis, the SVR rate was just over 20%.10 Results of meta-analyses and single center studies are only slightly more encouraging.11, 12
Developing safe and effective treatment of posttransplant HCV infection is one of the most important clinical challenges in our field. It has been with great anticipation that we have observed the steady progress of the lead candidate direct-acting antiviral agents, telaprevir and boceprevir, move through their respective clinical trial development, culminating in the Food and Drug Administration's (FDA) approval in May of 2011. These agents offer compelling and meaningful improvements in the efficacy of treatment of genotype 1 chronic HCV infection. In the preliminary summary of the presentations for telaprevir and boceprevir the FDA Antiviral Products Advisory Committee concluded (www.FDA.gov downloads posted May 5th 2011) that for
Caucasian patients who are treatment-naïve and have genotype 1 chronic HCV infection SVR rates were 75% (telaprevir) and 69% (boceprevir). For African American patients who are treatment-naïve with genotype 1 chronic HCV infection SVR rates were 65% (telaprevir) and 53% (boceprevir). Proportional increases in efficacy of these agents over peginterferon and ribavirin are even greater among treatment experienced patients. It is expected that many patients who have taken to the sidelines awaiting the routine availability of a more efficacious anti-HCV therapy will now step forward to consider treatment or re-treatment. It is likely, and with good cause, that the expectations among patients and providers are even greater among liver transplant recipients and their physicians. In this issue of HEPATOLOGY, Garg et al.,13 report findings of a drug-drug interaction study that suggests that for transplant recipients the protease inhibitors may add peril and promise in equal measure.
Telaprevir, is an inhibitor of the enzyme cytochrome P450 3A, which is responsible for the metabolism of both cyclosporine and tacrolimus. Garg et al., conducted a Phase I, open-label, nonrandomized, single sequence study to assess the effect of telaprevir coadministration on the pharmacokinetics of a single dose of cyclosporine and tacrolimus in two separate panels of 10 healthy volunteers each. The study design is somewhat unusual and merits detailed consideration. In Part A of this study, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg q8h). In Part B of the study by Garg et al., tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC) by approximately 4.6-fold and increased tacrolimus DN_AUC by approximately 70-fold. Similar effects were observed for elimination half-life (t1/2) of cyclosporine and tacrolimus.
The authors conclude that "telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly." The authors go on to point out that telaprevir has not been studied in organ transplant patients and its use in these patients is not recommended until the required studies have been completed and regulatory approval has been obtained. I couldn't agree more. The risk to transplant recipients of drug toxicities from inappropriate use of telaprevir cannot be overstated. Although drug-drug interaction studies with immunosuppressive agents have not been completed, as boceprevir is also known to be an inhibitor of cytochrome P450 3A4, the only safe course is to presume similar effects of boceprevir and telaprevir on calcineurin inhibitor pharmacokinetics.
It is highly responsible of Vertex to have conducted these drug-drug interaction studies and to have released the results to HEPATOLOGY so soon. The preparedness to conduct and publish these studies will, without question, save many patients from avoidable calcineurin inhibitor toxicities that would have inevitably resulted from a rush to administer telaprevir (or boceprevir) to liver transplant recipients. Sadly, the rush to treat is unlikely to be completely avoided.
We would do well to consider some of the limitations (distinct from criticisms) of the study by Garg et al., the results of which only hint at the potential for pharmacological misadventure. The first important limitation of the study is that the studies were conducted in healthy volunteers, not liver transplant recipients with recurrence of HCV. Both telaprevir and boceprevir are primarily cleared through hepatic metabolism, with only small amounts appearing in urine. As HCV infection has biologically meaningful effects on hepatic function, including inhibition of mitochondrial cytochromes,14 the effects of standard doses of telaprevir and boceprevir on CNI clearance are likely to be magnified in liver transplant recipients with HCV infection through reduced clearance and greater exposure to telaprevir and boceprevir. The effect of HCV on posttransplant cytochrome function is apparent clinically in the metabolism of tacrolimus and cyclosporine, which increases by approximately 30% following clearance of HCV in liver transplant recipients.15, 16 The effect of telaprevir/boceprevir administration on tacrolimus and cyclosporine levels and exposure is thus likely to be highly variable during the course of antiviral therapy. In addition, the effects of multiple co-administered doses of telaprevir (or boceprevir) cannot be accurately predicted from the study by Garg et al., as drug dosing only minimally overlapped in this study, probably before the maximal effect on tacrolimus and cyclosporine pharmacokinetics was achieved.
The reported magnitude of the effects of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus are greater than those reported for ritonavir and lopinavir, highly potent cytochrome P450 inhibitors.17 This has important implications. A tacrolimus dose of less than 1 mg/wk can be sufficient to maintain adequate blood tacrolimus concentrations in patients on ritonavir/lopinavir, with further dosing not required for 3 to 5 weeks, depending on liver function.18
It should also be noted that cyclosporine and tacrolimus are only two of the many agents that transplant recipients receive that are metabolized by cytochrome P450. Others include sirolimus, mycophenolate, macrolides, HIV antivirals, Ca2+ channel blockers, statins, analgesics and many more. The potential for medically significant drug interactions in liver transplant recipients who might receive telaprevir/boceprevir is almost limitless.
Should any liver transplant recipients receive these HCV protease inhibitors? I would counsel that three criteria should be met by any recipient who for whom telaprevir or boceprevir is prescribed: 1. There should be evidence of aggressive histological recurrence of HCV (e.g. ≤ stage 3 fibrosis) in the absence of hepatic decompensation; 2. The patient should be treated by physicians experienced in managing complex drug-drug interactions; and 3. Treatment should be in the context of informed consent by the recipient to participate in a protocol reviewed and approved by the appropriate Insititutional Review Board/Ethics Committee.
In Samuel Beckett's play Waiting for Godot, the protagonists Vladimir and Estragon wait endlessly in vain for Godot. The tragedy is that despite both claiming Godot as an acquaintance, they hardly know him and he never arrives. Physicians treating and patients with posttransplant recurrence of HCV have similarly waited for safer and more efficacious treatments. For Vladimir and Estragon the combination of impatience and ignorance was nearly lethal. Thanks to the study by Garg et al., we know enough about telaprevir and, by inference, boceprevir to avoid turning frustration into tragedy.
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Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus -
pdf attached
HEPATOLOGY, Vol. 54, No. 1, 2011
Varun Garg,1 Rolf van Heeswijk,2 Jee Eun Lee,1 Katia Alves,1 Priya Nadkarni,1 and Xia Luo1
From the 1Vertex Pharmaceuticals Inc., Cambridge, MA; and 2Tibotec BVBA, Beerse, Belgium.
ABSTRACT
The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC0-∞) by approximately 4.6-fold and increased tacrolimus DN_AUC0-∞ by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t1/2) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t1/2 of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. Conclusion: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life-threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained. (HEPATOLOGY 2011;)
The global prevalence of hepatitis C virus (HCV) infection is estimated to be 130 to 170 million, with approximately 3 to 4 million persons newly infected annually.1, 2 Approximately 38,000 new HCV cases occur annually in the United States alone.3 An estimated 75%-85% of infected individuals who do not clear the virus by 6 months develop chronic hepatitis that is often associated with serious liver disease.4, 5 Cirrhosis develops in 4%-20% of patients with chronic HCV infection, leading to hepatocellular carcinoma at an annual rate of 1%-5%.6 Furthermore, cirrhosis due to chronic HCV infection is the leading cause for liver transplantation; the incidence of such cases in the United States and Europe as of 2005 was approximately 30%-50%.7
Standard treatment for chronic HCV infection includes a combination of pegylated interferon and ribavirin, shown to cause sustained viral response in 45%-50% of patients treated.8-10 In recent clinical studies, the coadministration of telaprevir, an HCV protease inhibitor, with pegylated interferon/ribavirin resulted in substantial improvements in sustained viral response compared with pegylated interferon/ribavirin alone in patients with genotype 1 chronic HCV infection (treatment-naïve patients and in patients who had failed prior standard treatment).11-15 Patients who are not eligible for standard treatment often require liver transplant due to accompanying comorbid conditions.16 Recurrence of HCV infection occurs in 100% of liver transplantations if not eradicated prior to transplantation.17 Cyclosporine and tacrolimus are immunosuppressants with narrow therapeutic ranges used in the postoperative phase of liver or kidney transplants to prevent allograft rejection. Cyclosporine and tacrolimus are substrates of both cytochrome P450 3A (CYP3A), the primary enzyme responsible for their metabolism,18, 19 and P-glycoprotein (P-gp), a transmembrane transporter.20, 21 Telaprevir is a CYP3A4 substrate and inhibitor and has the potential to saturate or inhibit P-gp in the gut (data on file, Vertex Pharmaceuticals Inc.). Therefore, coadministration with telaprevir may increase the systemic exposure to cyclosporine and tacrolimus. The current study was designed to gain an understanding of the effect of telaprevir on the single-dose pharmacokinetic (PK) parameters of tacrolimus and cyclosporine to provide guidance for dose adjustments of these drugs prior to initiation of trial(s) in transplant patients.
RESULTS
Disposition and Demographics.
The first volunteer signed the informed consent form in January 2010, and the last volunteer completed the last visit in April 2010. In Part A, all 10 volunteers received at least one dose of cyclosporine and nine volunteers received at least one dose of cyclosporine coadministered with telaprevir. Mean (SD) volunteer age was 45.8 (9.19) years, height was 167 (11.8) cm, weight was 68.5 (11.6) kg, and body mass index was 24.4 (2.56) kg/m2. The majority of volunteers were females (70%) and white (80%).
In Part B, all 10 volunteers received at least one dose of tacrolimus administered alone and nine volunteers received at least one dose of telaprevir. One volunteer was withdrawn due to noncompliance with study procedures. Mean (SD) volunteer age was 38.0 (11.0) years, height was 175 (6.73) cm, weight was 77.4 (11.7) kg, and body mass index was 25.4 (3.53) kg/m2. All volunteers were male (100%) and the majority were white (70%).
Cyclosporine Pharmacokinetics.
The dose-normalized mean (SD) blood concentration-time profiles for cyclosporine administered either alone (day 1, period 1) or with telaprevir (days 1 and 8, period 2) are presented in Fig. 1. The dose-normalized concentrations of cyclosporine were higher when coadministered with telaprevir than for cyclosporine administered alone. Without dose normalization, the cyclosporine concentrations were lower when coadministered as a 10-mg dose with telaprevir than following administration of a 100-mg dose of cyclosporine alone (concentration-time profile without dose normalization not shown). Cyclosporine concentration-time profiles were comparable on day 1, period 2 and day 8, period 2, when a 10-mg dose of cyclosporine was administered with either a single dose of telaprevir or at steady-state telaprevir.
The mean (SD) PK and statistical parameters for cyclosporine administered either alone (100-mg dose; day 1, period 1) or with telaprevir (10-mg dose; days 1 and 8, period 2) are summarized in Table 1. In Part A, a comparison of PK parameters when cyclosporine was administered alone versus coadministered with telaprevir indicated that median tmax of cyclosporine increased from 1.50 hours on day 1, period 1 to 2.50 hours on both days 1 and 8, period 2; mean Vz/F changed from 955 L on day 1, period 1 to 1,010 L on day 1, period 2 and 735 L on day 8, period 2; mean CL/F decreased from 56.3 L/h on day 1, period 1 to 14.3 L/h on day 1, period 2 and 12.5 L/h on day 8, period 2; and mean t1/2 increased from 12.0 hours on day 1, period 1 to 52.5 hours on day 1, period 2 and 42.1 hours on day 8, period 2. The DN_Cmax GLS mean ratios (90% CI) for cyclosporine coadministered with telaprevir were 1.36 (1.12, 1.65) on day 1, period 2 and 1.32 (1.08, 1.60) on day 8, period 2 compared to cyclosporine administered alone. Similarly, the DN_AUC0-∞ GLS mean ratios (90% CI) for cyclosporine coadministered with telaprevir were 4.11 (3.49, 4.85) on day 1, period 2 and 4.64 (3.90, 5.51) on day 8, period 2 compared to cyclosporine administered alone on day 1, period 1, indicating a significant effect of a single dose and steady-state telaprevir on the PK of cyclosporine.
Tacrolimus Pharmacokinetics.
The dose-normalized mean (SD) blood concentration-time profiles for tacrolimus administered either alone (2-mg dose; day 1, period 1) or with telaprevir (0.5-mg dose; day 8, period 2) are presented in Fig. 2. Tacrolimus concentrations were considerably higher when coadministered with telaprevir than for tacrolimus administered alone.
The mean (SD) PK and statistical parameters for tacrolimus administered either alone (2-mg dose; day 1, period 1) or with telaprevir (0.5-mg dose; day 8, period 2) are summarized in Table 2. In Part B, a comparison of PK parameters when tacrolimus was administered alone versus coadministered with telaprevir indicated that median tmax of tacrolimus increased from 2.25 hours on day 1, period 1 to 3.03 hours on day 8, period 2; mean Vz/F decreased from 1,910 L on day 1, period 1 to 106 L on day 8, period 2; mean CL/F decreased from 32.0 L/h on day 1, period 1 to 0.48 L/h on day 8, period 2; and mean t1/2 increased from 40.7 hours on day 1, period 1 to 196 hours on day 8, period 2. The DN_Cmax GLS mean ratio (90% CI) for tacrolimus coadministered with telaprevir was 9.35 (6.73, 13.0) on day 8, period 2 compared to tacrolimus administered alone (day 1, period 1). Similarly, the DN_AUC0-∞ GLS mean ratio (90% CI) for tacrolimus coadministered with telaprevir was 70.3 (52.9, 93.4) on day 8, period 2 compared to tacrolimus administered alone (day 1, period 1), indicating a significant effect of telaprevir on the PK of tacrolimus.
Plasma Pharmacokinetics of Telaprevir.
Mean (SD) PK parameters for telaprevir when coadministered with either cyclosporine or tacrolimus are shown in Table 3. Steady-state concentrations of telaprevir on day 8, period 2 were similar when telaprevir was coadministered with either cyclosporine or tacrolimus. Steady-state exposure of telaprevir reported in this study was comparable with historical data.22
Safety.
In Part A, adverse events of mild vessel puncture site pain (n = 1), mild pharyngitis (n = 1), mild accidental needle stick (n = 1), and moderate neutropenia (n = 1) occurred when cyclosporine was administered alone. Moderate neutropenia led to premature discontinuation of the volunteer from the study. Adverse events of mild dyspepsia (n = 1); mild rash (n = 2); mild herpes simplex (n = 1); mild contusion (n = 1); mild blood creatine phosphokinase increase (n = 1); mild somnolence (n = 1); and mild vaginal discharge (n = 1) occurred when cyclosporine was coadministered with telaprevir. Dyspepsia and rash were considered by the study investigator to be possibly related to the study drugs.
In Part B, an adverse event of mild constipation (n = 1) occurred when tacrolimus was administered alone. Adverse events of mild pruritus (n = 1) and mild excoriation (n = 1) occurred when tacrolimus was coadministered with telaprevir.
No serious, life-threatening, or severe adverse events occurred in any group. There were no notable clinically significant trends for any of the chemistry parameters, hematology parameters, vital signs, 12-lead electrocardiograms, or physical examination findings.
Discussion
The primary objective of this study was to evaluate the effect of telaprevir on the PK of single doses of cyclosporine and tacrolimus in healthy volunteers. The 100-mg cyclosporine dose and the 2-mg tacrolimus dose were chosen as they were well tolerated in healthy volunteers in previous studies.23, 24 The doses of cyclosporine and tacrolimus were lowered when coadministered with telaprevir because of the potential for marked increase in cyclosporine and tacrolimus exposure.
Dose-normalized cyclosporine exposure increased significantly when coadministered with telaprevir compared to administration of cyclosporine alone: the dose-normalized Cmax increased by approximately 1.3- to 1.4-fold, dose-normalized AUC increased by approximately 4.1- to 4.6-fold, and mean t1/2 of cyclosporine increased approximately 4-fold following coadministration of cyclosporine with either a single dose or steady-state telaprevir. Cyclosporine exposure was comparable when administered with either a single dose of telaprevir (day 1, period 2) or when telaprevir reached steady-state (day 8, period 2), suggesting an absence of time-dependent inhibition of cyclosporine metabolism by telaprevir.
The effect of telaprevir coadministration was much greater with tacrolimus: the dose-normalized Cmax increased by approximately 9.3-fold, dose-normalized AUC increased by approximately 70-fold, and the mean t1/2 of tacrolimus increased approximately 5-fold. Because of the long t1/2 of tacrolimus and the long time it would take to wash out any effect of telaprevir on its PK, the interaction with tacrolimus was only evaluated with steady-state telaprevir. It is unknown whether the magnitude of the effect of telaprevir on tacrolimus would be similar after the first dose of telaprevir, as seen with cyclosporine.
These results are significant and indicate that without understanding the adjustments required for dose and/or dosing frequency of cyclosporine and tacrolimus, telaprevir coadministration could lead to serious or life-threatening adverse events. The mechanism for the greater effect of telaprevir on the PK of tacrolimus compared to cyclosporine is unknown, but may be related to lower bioavailability of tacrolimus (≈18%) in healthy volunteers,19 making it more susceptible to CYP3A and/or P-gp inhibition in the gut and during first-pass metabolism. This is also suggested by the 9.3-fold increase in the tacrolimus Cmax and the sharp decrease in the mean (SD) apparent volume of distribution (Vz/F) of tacrolimus from 1,910 (859) L when administered alone to 106 (34) L (Table 2) in the presence of telaprevir (i.e., an increase in oral bioavailability, F, without a proportional change in volume of distribution, Vz, may decrease the ratio, Vz/F closer to the reported value of Vz, corrected for F, in healthy volunteers of 1.94 L/kg19). In contrast, there was no apparent change in the Vz/F of cyclosporine after the first or last telaprevir dose (Table 1) compared to cyclosporine administered alone, suggesting that bioavailability of cyclosporine was not changed in the presence of telaprevir, consistent with the observed modest effect of telaprevir on the Cmax of cyclosporine. However, the bioavailability of cyclosporine varies considerably depending on patient population (ranging from <10% in liver transplant patients to 89% in some kidney transplant patients).18 Therefore, the effect of telaprevir on cyclosporine concentrations in liver transplant patients may differ from that observed in this healthy volunteer study, and close monitoring of cyclosporine concentrations to guide individual dose adaptations would be necessary during coadministration.
The decrease in hepatic clearance and increase in t1/2 of both cyclosporine and tacrolimus upon telaprevir coadministration suggests that systemic clearance of these immunosuppressants was also reduced by telaprevir. The effect of telaprevir on hepatic transporters that could have contributed to lower clearance or enhanced absorption is unknown.
Notably, in this study the effect of steady-state telaprevir on the PK of cyclosporine or tacrolimus was evaluated only at single doses of these immunosuppressants. Because the elimination half-lives increased significantly for both cyclosporine and tacrolimus when telaprevir was coadministered, without proper adjustment of dose and dosing interval of these immunosuppressants, further increases in blood exposure may occur when multiple doses of these drugs are coadministered with telaprevir. However, studies of telaprevir with multiple doses of cyclosporine and tacrolimus have not been performed.
The effects of telaprevir on cyclosporine and tacrolimus exposure were similar to that reported for human immunodeficiency virus (HIV) protease inhibitors known to be potent CYP3A inhibitors, where significant reductions in dose and/or dosing interval of immunosuppressants were needed to achieve the desired range of trough concentrations, based on frequent monitoring of trough concentrations of the immunosuppressants.25 For example, addition of lopinavir/ritonavir (n = 7 patients) reduced tacrolimus dose by 99% to maintain tacrolimus concentrations within the therapeutic range.26 Similarly, during coadministration of Highly Active Antiretroviral Therapy (HAART) regimens with ritonavir-boosted HIV protease inhibitors, daily cyclosporine doses were reduced by 80%-95% to maintain cyclosporine exposure at pre-HAART levels. Because of the flat absorption/elimination profiles of cyclosporine during combination with ritonavir-boosted HAART therapy, cyclosporine exposure could be reliably monitored long-term by measuring cyclosporine trough concentrations.27 Treatment of posttransplant patients coinfected with HIV/HCV with antiretrovirals and telaprevir could be even more challenging, depending on the drugs involved. Telaprevir levels are not significantly affected by ritonavir28; however, whether the net effect of antiretroviral drugs on cyclosporine and tacrolimus PK would be similar or different is hard to predict, as these drugs may have their own effects. The PK of tacrolimus and cyclosporine may also vary based on CYP3A5 genotype.29 Therefore, the effect of telaprevir on these drugs may also vary based on CYP3A5 genotype.
Although cyclosporine is a CYP3A and P-gp inhibitor,18 the effects of a single cyclosporine dose on systemic telaprevir exposure were considered negligible, because the cyclosporine dose (10 mg) was low and administered 2 hours after telaprevir administration. This study was not designed to test the effect of cyclosporine and tacrolimus on telaprevir exposure. However, telaprevir steady-state exposure in Parts A and B were similar to previous Phase I studies,22 so it is unlikely that coadministration of cyclosporine or tacrolimus had a relevant effect on telaprevir exposure.
Food decreases cyclosporine and tacrolimus exposure (Cmax by 33% and 65%; AUC by 13% and 28%, respectively),18, 19 whereas telaprevir exposure increases with food. Telaprevir was administered 30 minutes after the start of a meal and cyclosporine or tacrolimus were administered 2 hours after telaprevir during coadministration. Volunteers refrained from further food or drink during the period between administration of telaprevir and cyclosporine or tacrolimus. This approach was used to minimize food effect on cyclosporine and tacrolimus exposure, while providing appropriate telaprevir dosing conditions. The extent to which simultaneous telaprevir administration with cyclosporine or tacrolimus in the fed state would impact these results is unknown.
Another important consideration about concomitant tacrolimus or cyclosporine use with telaprevir in organ transplant patients is that after telaprevir treatment is completed or stopped, its inhibitory effect on CYP3A/P-gp would wear off and doses of immunosuppressant would need readjustments. Estimates of the recovery time of CYP3A activity vary widely30 and precise timing for CYP3A activity to resume to the levels before the start of telaprevir is unknown. Therefore, careful blood concentration monitoring of immunosuppressants will be needed for approximately 2 weeks after telaprevir is stopped.
Besides cyclosporine and tacrolimus, other immunosuppressants that are likely to have a significant interaction with telaprevir include those known to have increased exposures when coadministered with strong CYP3A inhibitors, such as sirolimus and everolimus. Exposure of corticosteroids known to be metabolized by way of CYP3A may also increase in the presence of strong CYP3A inhibitors. However, studies with these drugs in combination with telaprevir have not been conducted.
Finally, telaprevir has not been studied in pre-, post-, or peritransplant patients. The degree of the interaction with calcineurin inhibitors reported here suggests potential implications for patient safety. Telaprevir should not be administered to these patients, because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained.
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