Hp122-03-review (07p).p65

Drug interactions with boceprevir and telaprevir. CONCISE REVIEW
A review of drug interactions with boceprevir and telaprevir:
implications for HIV and transplant patients
Kyle J. Wilby,* Erica D. Greanya,† Jo-Ann E. Ford,‡ Eric M. Yoshida,§ Nilufar Partovi|| * BSP, ACPR, Doctor of Pharmacy Candidate, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
†† BScPharm, ACPR, PharmD, Clinical Pharmacy Specialist in Solid Organ Transplantation, Vancouver General Hospital; and Clinical Associate Professor, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
‡‡ RN, MsN, Associate Director, Clinical Research and Associate Director, BC Hepatitis Program, Gordon & Leslie Diamond Health Care Centre, Vancouver, British Columbia, Canada.
§ MD, MHSc, FRCP(C), FACP, FACG. Professor of Medicine and Head, Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada.
|| Pharm D, Coordinator, Clinical Pharmacy Services and Clinical Pharmacy Specialist in Transplantation and Immunology, Vancouver General Hospital; and Clinical Associate Professor, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
Purpose. Chronic hepatitis C virus (HCV) is a major problem affecting up to 170 million people worldwide.
Two protease inhibitors have recently been approved that will revolutionize treatment. Our objective was
to summarize and evaluate the literature pertaining to the pharmacokinetics of boceprevir and telaprevir,
in order to provide clinicians with insight into the management of actual and potential drug interactions.
Summary. A standardized search using MEDLINE (1948-November 2011), EMBASE (1980-November 2011), IPA
(1970-November 2011), Google, and Google Scholar that combined the search terms boceprevir, telaprevir,
pharmacokinetics, drug interaction, and drug metabolism was performed. Manual reference searches of
chosen articles were completed. Monographs and articles, conference proceedings, and abstracts were
evaluated. Boceprevir and telaprevir are both substrates and inhibitors of cytochrome P450 3A4 and tela-
previr is a substrate of p-glycoprotein. Levels of boceprevir are decreased in patients taking efavirenz but
effects with other antiretrovirals are minimal or unknown. Coadministration with efavirenz may compromise
telaprevir levels and should be avoided. Telaprevir may increase levels of cyclosporine, tacrolimus, atorvas-
tatin, and amlodipine, which may expose patients to increased adverse effects. Conclusions. Significant
drug-drug interactions occur with both boceprevir and telaprevir. Until studies are reported and expe-
rience is gained with these agents, clinicians will need to be careful when administering in high-risk popu-
lations and those receiving chronic therapy with interacting agents. Studies are urgently needed in HIV
patients taking antiretrovirals and patients taking chronic immunosuppresion as these populations are at
increased risk of experiencing clinically significant interactions.
Key words. Hepatitis. Hepatitis C. Protease inhibitors.
hosis which may lead to transplantation or prema- ture death. These complications are associated with Chronic hepatitis C virus (HCV) is a major health significant morbidity, as well as stress and psycho- problem affecting up to 170 million people world- logical suffering. The only treatment available prior wide.1 While many are not aware of infection, others to 2011 was pegylated interferon and ribavirin.2 become symptomatic and go on to develop liver cirr- When administered together for 48 weeks, these agents were able to produce clinical cure in approxi- mately 40-50% of patients with genotype-1 infec- Correspondence and reprint request: Dr. Nilufar Partovi
tion.3,4 For those who failed previous treatment, the Department of Pharmacy. Vancouver General Hospital likelihood of success with a second course, while 855 West 12th Avenue. Vancouver, BC, V5Z 1M9, Canada reasonable for those who relapsed after previous res- ponse, is dismal at < 20% for those who were non- Manuscript received: November 11, 2011. responders.5 The low rates of success in genotype 1 Manuscript accepted: November 25, 2011. infection meant any patients had to manage compli- cations of liver disease, with significant morbidity The objective of this review is to summarize and and mortality, or await transplantation. Of those evaluate the literature pertaining to the pharmaco- with chronic HCV infections, two special groups, kinetics of boceprevir and telaprevir in order to those with HIV co-infection and those who have un- provide clinicians with insight into the manage- dergone liver transplantation, where post-transplant ment of actual and potential drug interactions. As HCV recurrence is universal, are well-recognized to of this writing, neither boceprevir nor telaprevir have an accelerated natural history of the disease.6,7 are licensed for use in patients co-infected with Unfortunately, treatment with pegIFN and ribavirin HIV or post-transplantation. Definitive clinical in these groups is far less likely to be associated trials in these special populations are either on- with treatment success compared to the non-HIV going or are in the planning stages. Given the seve- and non-transplant patient populations.8,9 rity of HCV infection in the post-transplant setting In 2011, two new licensed agents have changed and in patients co-infected with HIV, it is anticipa- the management of hepatitis C infection. Boceprevir ted that some patients from these special groups and telaprevir are both orally administered inhibi- will be considered for off-label use of these antiviral tors of the HCV protease NS 3/4A. When combined with peginterferon and ribavirin for genotype-1 in- fection, success rates have increased to 68-75% for Data sources
treatment naïve and doubled to 60-65% of treatment experienced patients.10-13 Given the significant im- A standardized search using MEDLINE (1948-Au- provements in response rates for these difficult to gust 2011), EMBASE (1980-August 2011), IPA treat patients, these protease inhibitors, in combina- (1970-August 2011), Google, and Google Scholar tion with peginterferon and ribavirin, are now the that combined the search terms boceprevir, telapre- best treatment option for the treatment of HCV ge- vir, pharmacokinetics, drug interaction, and drug metabolism was performed. Articles, conference pro- As with any new agent, the potential for drug- ceedings, and abstracts that described pharmacoki- drug interactions needs to be assessed. Both of these netics and drug-drug interactions between agents are substrates and inhibitors of the cytochro- boceprevir, telaprevir, and other agents were identi- me P450 3A (CYP3A) metabolic pathway.14,15 As fied. Manual reference searches of chosen articles many commonly used medications utilize the CYP3A were completed to identify articles missed by the metabolic pathway, the potential for many drug- electronic search. Monographs produced by the ma- drug interactions exists and the clinical significance of these interactions needs to be assessed to ensure Pharmacokinetics
Two populations of particular interest are pa- tients infected with the human immunodeficiency vi- Few pharmacokinetic studies have been comple- ted with boceprevir. According to manufacturer immunusuppression, such as solid organ transplant data, boceprevir is readily absorbed following oral patients. Many commonly used antiretrovirals for administration with a median time to maximum the treatment of HIV affect the CYP3A metabolic pa- serum concentration (Tmax) of 2 h. Food enhances thway, or are themselves substrates. The same is absorption up to 60% at steady-state but no effects also true for immunosuppressive agents. These were seen when assessed for meal type (fat content) agents have narrow therapeutic windows in which or timing in comparison to food intake (before, du- optimal efficacy and safety can be achieved. The im- ring, or after a meal). The mean apparent volume of pact of introducing an agent that may interact with distribution is 717 L and it is not highly protein HIV or immunosuppression therapy, such as boce- bound (75% after a single oral dose). Boceprevir is previr or telaprevir, may be significant, resulting in primarily metabolized by the aldoketoreductase treatment failure or development of serious adverse (AKR)-mediated pathway to inactive ketone metabo- events. As substrates of CYP3A, boceprevir and tela- lites. It is also a substrate of CYP3A4/5 and is an in- previr are also vulnerable to the influence of antire- hibitor of this enzyme. It has a mean plasma trovirals and immunosuppressants on this pathway.
half-life of 3.4 h and therefore reaches steady state It is therefore essential to characterize the clinical after approximately 1 day of three times a day do- significance of any potential interaction, in order to sing. There is minimal elimination of unchanged achieve the best possible patient outcomes.
Drug interactions with boceprevir and telaprevir. Telaprevir is administered orally and is a subs- (a CYP3A inducer), Cmin levels of boceprevir decrea- trate of the gastrointestinal efflux transporter sed by 44%.16 It is unknown if this would result in p-glycoprotein. Food increases absorption and it HCV treatment failure so coadministration should be is recommended to be taken with food to maximize avoided until further evaluations are complete. Teno- this benefit. It is minimally bound to plasma proteins fovir, a nucleotide analog reverse transcriptase inhibi- and has an approximate apparent volume of distri- tor (NRTI) does not appear to significantly alter the bution of 252 L. It is extensively metabolized by pharmacokinetics of boceprevir.16 Similarly, the HIV hepatic hydrolysis, reduction and oxidation through protease inhibitor (PI) ritonavir does not appear to in- the CYP3A enzyme pathway. It also acts as a potent teract with boceprevir.16 However, the effects of HIV inhibitor of the CYP 3A enzyme. It is primarily protease inhibitors with or without ritonavir boosting eliminated in the feces and has a mean plasma half- are unknown and should be avoided until experience is There are currently no available drug interaction DRUG INTERACTIONS
studies with immunosuppressant agents. Plasma concentrations of the calcineurin inhibitors cyclos- Boceprevir
porine and tacrolimus would be expected to increase due to inhibition of CYP3A by boceprevir. Cyclospo- By utilizing multiple routes of metabolism (aldo- rine is a substrate of CYP 3A but is also an inhibi- ketoreductase and CYP3A), boceprevir is less prone tor,17 and therefore may potentially increase the to drug interactions. A summary of selected interac- levels of boceprevir, resulting in increased frequency tions is reported in table 1. Manufacturer studies of adverse events including anemia. If coadministra- have shown coadministration with aldoketoreducta- tion cannot be avoided, careful therapeutic drug mo- se inhibitors (ibuprofen and diflunisal) does not re- nitoring, and likely empiric dose reduction of these sult in clinically significant changes to boceprevir agents is indicated to ensure optimal efficacy and exposure.14 There is therefore no need to avoid avoid dose related toxicities. While no data is availa- ble, it is our opinion that co-administration of boce- Drug interaction studies have assessed pharmacoki- previr and the mammalian target of rapamycin netic changes between boceprevir and three antiretro- inhibitor (mTOR) sirolimus should be avoided. The virals. When coadministered with the non-nucleoside long half-life of sirolimus of 60 h, as well as the sig- reverse transcriptase inhibitor (NNRTI) efavirenz nificant adverse effect of anemia would make concu- Table 1. Established and theoretical drug-drug interactions with boceprevir.
Effects unknown in combination with otherHIV protease inhibitors.
Expected increase in cyclosporine exposure.
Therapeutic drug monitoring indicated for dose optimization.
Expected increase in tacrolimus exposure.
Therapeutic drug monitoring indicated for dose optimization.
Expected increase in sirolimus exposure.
Therapeutic drug monitoring indicated for dose optimization.
Non-hormonal contraception should be used while taking boceprevir.
n Increases in pharmacokinetic parameters (maximum concentration, minimum concentration, area under the curve).
p Decreases in pharmacokinetic parameters (maximum concentration, minimum concentration, area under the curve).
rrent therapy with the HCV protease inhibitors diffi- ceprevir. Unfortunately, no data is available asses- cult to manage and may provide additive toxicity.18 sing theoretical interactions with potent inducers Potential interactions exist between boceprevir (eg. rifampin, phenytoin) or inhibitors (eg. clari- and other agents that utilize and affect the CYP3A thromycin, voriconazole) of the CYP system.
pathway. When coadministered with ketoconazole, a potent CYP3A inhibitor, boceprevir exposure was Telaprevir
increased (131% increase in AUC, 41% increase in Cmax).16 The clinical effects of this interaction are Telaprevir is both a substrate and potent inhibi- unknown. Oral contraceptive agents also utilize the tor of CYP3A and is prone to many drug-drug inte- CYP3A pathway. Drospirenone levels increased ractions with other agents that utilize or affect this metabolic pathway. It may displace medication from Cmax increased 99% and 57% respectively) and put plasma proteins, which may decrease plasma con- patients at risk of adverse events.16 These agents centrations of concurrently administered medications should not be used concomitantly. Conversely, which are highly protein bound.15 It is also a subs- ethinyl estradiol concentrations were minimally trate of p-glycoprotein and may inhibit or saturate affected (AUC decrease of 24%).16 Until more infor- this transporter and higher concentrations of subs- mation is obtained, use of non-hormonal methods of trates may be observed. Few studies have assessed birth control is preferred during treatment with bo- clinical effects of these interactions but recommen- Table 2. Established and theoretical drug-drug interactions with telaprevir.
Avoid combination. Current trial assessing efficacy and safety of increased telaprevir doses.
No dosage adjustment necessary.
Not suitable for ritonavir-boosting.
Avoid combination due to HCV treatment failure.
Avoid combination due to HIV/HCV treatment failure.
Avoid combination due to HIV/HCV treatment failure.
safety being evaluated in ongoing clinical trial.
4-fold increase in cyclosporine exposure.
Therapeutic drug monitoring indicated fordose optimization.
Possible 70-fold increase in tacrolimus exposure.
Expected increase in sirolimus exposure.
Therapeutic drug monitoring indicated for doseoptimization.
If combination unavoidable, use lowest possible doses Non-hormonal contraception should be used while n Increases in pharmacokinetic parameters (maximum concentration, minimum concentration, area under the curve). p Decreases in pharmacokinetic parame-ters (maximum concentration, minimum concentration, area under the curve).
Drug interactions with boceprevir and telaprevir. dations can be made based on preliminary data.
tions of telaprevir. Dose-normalized comparisons When initiating any potentially interacting agent, were significantly increased for both Cmax and the most current data should be obtained to ensure AUC of cyclosporine when administered with tela- appropriate dosage adjustments and monitoring oc- previr. Cmax increased 1.3 times baseline and AUC curs. Potential and actual drug interactions for increased 4.5 fold from baseline. The mean half-life commonly used agents are presented in table 2.
of cyclosporine increased from 12 h at baseline Coadministration with antiretrovirals is concer- to 53 h at steady state dosing, a greater than 4 fold ning for both efficacy and safety of HIV and HCV change. Although telaprevir concentrations were therapy. Initial studies with the NNRTI efavirenz obtained, samples were not taken in the absen- show significant decreases in telaprevir concentra- ce of cyclosporine and conclusions cannot be tions and this combination should be avoided.19 This made regarding cyclosporine’’s effect on its phar- effect is likely due to induction effects of efavirenz on CYP 3A.20 According to subsequent analysis, it For tacrolimus, in a similar fashion, healthy vo- was determined that higher doses of telaprevir may lunteers were given a 2 mg dose of tacrolimus for overcome the metabolic induction effects of efavi- pharmacokinetic assessment in the absence of tela- renz. This belief is currently being confirmed in cli- previr. A minimum washout period of 14 days occu- nical trials. When coadministered with the HIV PI’’s rred and then patients received telaprevir 750 mg fosamprenavir, lopinavir, and darunavir (all boosted every 8 h for days 1 to 13. On day 8, representing with ritonavir), concentrations of telaprevir were steady-state dosing of telaprevir, a 0.5 mg dose of ta- significantly decreased and concentrations of fosam- crolimus was given. Dose-normalized comparisons prenavir and darunavir were decreased.19 The me- were significantly increased for both Cmax and AUC chanism of this interaction is unknown.
of tacrolimus. Cmax increased 9.3-fold and AUC in- Combination with telaprevir should be avoided to creased 70-fold from baseline. The mean half-life of reduce failure of HIV viral suppression and HCV tacrolimus increased from 40 h at baseline to 196 h treatment failure. Atazanavir-based regimens are at steady state dosing. Unfortunately no baseline less affected than the other PI’’s.19 Combination regi- data was obtained for telaprevir concentrations to mens of telaprevir with ritonavir-boosted atazanavir assess the affect of tacrolimus on its pharmacokine- are currently under investigation in clinical trials.
tics. However, given less significant inhibition of It was initially believed that telaprevir could be CYP 3A4 with tacrolimus as compared to cyclospori- boosted by low-dose ritonavir to maximize exposure ne, there is potential for less impact on teleprevir and decrease dosing frequency. Preliminary studies in rat and human hepatic microsomes showed rito- The results of this study confirm significant inte- navir significantly inhibited the metabolism of tela- ractions exist between cyclosporine, tacrolimus and previr.21 These findings were assessed in a clinical telaprevir that may expose patients to toxicity from trial with healthy volunteers and it is reported that calcineurin inhibitors. No major adverse events ritonavir has minimal affect on steady-state telapre- were recorded during the study, however, due to the vir concentrations.22 Therefore, ritonavir boosting minimal dose design this is not an unexpected fin- of telaprevir is not a viable therapeutic option.
ding.23 An extended dosing regimen, without ade- A pharmacokinetic study was identified that as- quate dose adjustment of calcineurin inhibitor, is sessed the effect of telaprevir on cyclosporine and likely to result in undesired effects, such as nephro- tacrolimus in healthy volunteers.23 For cyclospori- toxicity. While some are advocating that the combi- ne, pharmacokinetic parameters were mearsured nation of these agents should be avoided until safe after receiving a single oral dose of cyclosporine dosing regimens are established,23 it is likely that 100 mg in the absence of teleprevir. After a manda- these interactions will be encountered, so clinicians tory eight day washout period, patients received need to be aware and provide appropriate empiric 750 mg of telaprevir every eight hours for days 1 dose adjustment of calcineurin inhibitors at initia- through 11 and a 10 mg daily dose of cyclosporine tion of PI therapy followed by very close therapeutic was given on days 1 and 8. Through measurement drug monitoring. In fact, the degree of drug interac- of whole-blood concentrations of cyclosporine and tion may require dosing of cyclosporine and tacroli- plasma concentrations of telaprevir on days 1 and mus intermittently based on drug levels. Logistics of 8, pharmacokinetic profiles of both cyclosporine this approach may be difficult depending on availabi- and teleprevir were captured. The concentrations lity and turn around time for therapeutic drug moni- obtained on day 8 represent steady-state concentra- A pharmacokinetic study was recently completed HIV patients are especially vulnerable to drug- that assessed interactions with amlodipine and ator- drug interactions due to the complexity of treatment vastatin, both substrates of CYP3A4.25 Healthy vo- regimens and the importance of maintaining suppres- lunteers were given single doses of amlodipine and sed HIV-viral loads. Disruptions in therapy could atorvastatin at baseline and again at steady state of compromise HIV care and result in development of telaprevir. For amlodipine, the mean Cmax and resistance to antiretrovirals, exposure to undesired AUC increased 1.27 and 2.79-fold respectively. The adverse effects, and failure of therapy. Ongoing clini- mean half-life increased from 41 to 95 h, which was cal trials have been designed to help guide future attributed to decreases in clearance. For atorvasta- treatment decisions. Until then, clinicians will need tin, the mean Cmax and AUC were increased 10.6 to weigh the benefits and risks of using boceprevir or and 7.88-fold respectively. There was no statistically telaprevir in patients taking antiretrovirals, compa- significant difference in half-life. Metabolites of ator- red to using standard therapy alone.
vastatin also appeared to be affected by telaprevir Transplant patients and those requiring immuno- but limited data and large variability inhibit inter- suppression are also at high risk for clinically signi- pretation of the results. Study investigators noted ficant drug interactions. Tacrolimus, a first-line no major adverse events but this study also utilized agent, is especially increased by telaprevir to expo- a single dose design. The potential for serious adver- sure 70-fold that of regular dosing.23 Cyclosporine se events to occur with chronic dosing has contrain- was also affected, although to a lesser extent. These dicated the use of atorvastatin with telaprevir.
findings have important implications for patients.
Amlodipine should be avoided if possible but may be Increased exposure puts patients at risk of serious used in lower doses and titrated carefully, in order and life-threatening adverse drug reactions. It is to avoid supra-therapeutic effects and toxicity.
therefore essential that dose optimization studies be An interaction of great therapeutic importance is completed to prevent these adverse consequences.
coadministration with oral contraceptive pills.
For any patient using these agents in combination, Ethinyl estradiol Cmax, Cmin, and AUC decreased therapeutic drug monitoring of immunosuppressant by 26, 37, and 28% respectively when both telaprevir levels is essential for management of care.
and ethinyl estradiol were at steady state.26 Corres- This review summarized the available pharmaco- ponding increases in luteinizing hormone and folli- kinetic literature pertaining to boceprevir and tela- cle stimulating hormone were seen in relation to previr and associated drug interactions. The major these changes in estrogen levels. Non-hormonal con- limitation of this review is the lack of published traception should be recommended while patients data and the reliance on unpublished data from ma- are taking telaprevir, in order to prevent treatment nufacturer sources or abstracts to guide treatment decisions. Until future studies are reported and ex- perience is gained with these agents, clinicians will need to be especially careful when administering in high-risk populations and those receiving chronic Significant drug-drug interactions occur with therapy with interacting agents. Studies are urgent- both boceprevir and telaprevir. We have reviewed ly needed in HIV patients taking antiretrovirals and and discussed potential and confirmed interactions patients taking chronic immunosuppresion as these and have provided recommendations for therapy populations are at increased risk of experiencing cli- where appropriate. While boceprevir is less suscep- tible to metabolic interactions due to multiple pa- thway metabolism, clinicians need to be cautious CONFLICT OF INTERESTS
when using this agent in combination with other agents that use or affect CYP3A. Telaprevir is a po- In regards to hepatitis C, Dr. Eric Yoshida has tent CYP3A inhibitor and has greater potential to been an investigator of clinical trials sponsored by: cause significant drug-drug interactions. While Boeringher Ingelheim Inc., Gilead Sciences Inc., data is available assessing some potential interac- Hoffman LaRoche Inc., Human Genome Sciences, tions, clinicians need to be especially careful when Merck Inc., Norvartis Inc., Pfizer Inc., Schering initiating this agent and should frequently monitor Plough Inc., Tibotec Inc., Vertex Pharmaceuticals the pharmacokinetic literature to become aware of Inc. He has received honouraria for CME lectures updated dosage recommendations and contraindica- sponsored by Merck Inc and Hoffman LaRoche Inc.
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096_05lug2012 - dedicato a coloro che assumono il coumadin

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