Download PDF
Drug Res (Stuttg) 2022; 72(06): 319-326
DOI: 10.1055/a-1835-1690
Original Article

Statins Increase the Bioavailability of Fixed-Dose Combination of Sofosbuvir/Ledipasvir by Inhibition of P-glycoprotein

K.S. Abdelkawy
1   Department of Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
,
Fathalla Belal
2   Department of Analytical Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
,
AbdelazizE Abdelaziz
3   Department of Pharmaceutical Technology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
,
H. A. Elmekawy
1   Department of Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
,
M. Y. Abdelgaied
4   Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
,
N. M. El-Khodary
1   Department of Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
› Author Affiliations Funding This work was supported by the Research Center of Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Egypt.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Background Coadministration of statins and direct acting antiviral agents is frequently used. This study explored the effects of both atorvastatin and lovastatin on pharmacokinetics of a fixed-dose combination of sofosbuvir/ledipasvir “FDCSL”.

Methods 12 healthy volunteers participated in a randomized, three-phase crossover trial and were administered a single atorvastatin dose 80 mg plus tablet containing 400/90 mg FDCSL, a single lovastatin dose 40 mg plus tablet containing 400/90 mg FDCSL, or tablets containing 400/90 mg FDCSL alone. Liquid chromatography-tandem mass spectrometry was used to analyze plasma samples of sofosbuvir, ledipasvir and sofosbuvir metabolite “GS-331007” and their pharmacokinetic parameters were determined.

Results Atorvastatin caused a significant rise in sofosbuvir bioavailability as explained by increasing in AUC0−∞ and Cmax by 34.36% and 11.97%, respectively. In addition, AUC0-∞ and Cmax of GS-331007 were increased by 73.73% and 67.86%, respectively after atorvastatin intake. Similarly, co-administration of lovastatin with FDCSL increased the bioavailability of sofosbuvir, its metabolite (AUC0-∞ increase by 17.2%, 17.38%, respectively, and Cmax increase by 12.03%, 22.24%, respectively). However, neither atorvastatin nor lovastatin showed a change in ledipasvir bioavailability. Hepatic elimination was not affected after statin intake with FDCSL. Compared to lovastatin, atorvastatin showed significant increase in AUC0-∞ and Cmax of both sofosbuvir and its metabolite.

Conclusions Both atorvastatin and lovastatin increased AUC of sofosbuvir and its metabolite after concurrent administration with FDCSL. Statins’ P-glycoprotein inhibition is the attributed mechanism of interaction. The increase in sofosbuvir bioavailability was more pronounced after atorvastatin intake. Close monitoring is needed after co-administration of atorvastatin and FDCSL.

Key words

Atorvastatin - Lovastatin - Ledipasvir - Sofosbuvir - GS-331007 - P-glycoprotein


Publication History

Received: 07 February 2022

Accepted: 19 April 2022

Article published online:
20 June 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 website WHO (2020) Hepatitis C; . https://www.who.int/news-room/fact-sheets/detail/hepatitis-c
    PubMed
  • 2 Afdhal N, Reddy KR, Nelson DR. et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. New England Journal of Medicine 2014; 370: 1483-1493
    CrossrefPubMedGoogle Scholar
  • 3 Wei L, Xie Q, Hou JL. et al. Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an open-label, phase 3b study. Hepatology 2018; 12: 126-132
    PubMedGoogle Scholar
  • 4 Mehellou Y, Rattan HS, Balzarini J. The ProTide Prodrug Technology: From the Concept to the Clinic: Miniperspective. Journal of Medicinal Chemistry 2017; 61: 2211-2226
    CrossrefPubMedGoogle Scholar
  • 5 Kattakuzhy S, Levy R, Kottilil S. Sofosbuvir for treatment of chronic hepatitis C. Hepatology International 2015; 9: 161-173
    CrossrefPubMedGoogle Scholar
  • 6 Li X, Liu Y, Xu B. et al. Evaluation of the pharmacokinetics and food intake effect of generic sofosbuvir in healthy Chinese subjects. International Journal of Clinical Pharmacology and Therapeutics 2020; 58: 230-241
    CrossrefPubMedGoogle Scholar
  • 7 Kirby BJ, Symonds WT, Kearney BP. et al. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir. Clinical Pharmacokinetics 2015; 54: 677-690
    CrossrefPubMedGoogle Scholar
  • 8 Noell BC, Besur SV. Andrew Sd. Changing the face of hepatitis C management–the design and development of sofosbuvir. Drug Design, Development and Therapy 2015; 9: 2367-2374
    PubMedGoogle Scholar
  • 9 German P, Mathias A, Brainard D. et al. Clinical pharmacokinetics and pharmacodynamics of ledipasvir/sofosbuvir, a fixed-dose combination tablet for the treatment of hepatitis C. Clinical Pharmacokinetics 2016; 55: 1337-1351
    CrossrefPubMedGoogle Scholar
  • 10 Sciences G (2015) HARVONI (ledipasvir and sofosbuvir)
    PubMed
  • 11 Gritsenko D, Hughes G. Ledipasvir/Sofosbuvir (harvoni): improving options for hepatitis C virus infection. Pharmacy and Therapeutics 2015; 40: 256-276
    PubMedGoogle Scholar
  • 12 German P, Mathias A, Brainard DM. et al. Drug–Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir. Clinical Pharmacokinetics 2018; 57: 1369-1383
    CrossrefPubMedGoogle Scholar
  • 13 Perlemuter G, Sabile A, Letteron P. et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. The FASEB Journal 2002; 16: 185-194
    CrossrefPubMedGoogle Scholar
  • 14 Domitrovich AM, Felmlee DJ, Siddiqui A. Hepatitis C virus nonstructural proteins inhibit apolipoprotein B100 secretion. Journal of Biological Chemistry 2005; 280: 39802-39808
    CrossrefPubMedGoogle Scholar
  • 15 Mirandola S, Realdon S, Iqbal J. et al. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology 2006; 130: 1661-1669
    CrossrefPubMedGoogle Scholar
  • 16 Alberstein M, Zornitzki T, Zick Y. et al. Hepatitis C core protein impairs insulin downstream signalling and regulatory role of IGFBP-1 expression. Journal of Viral Hepatitis 2012; 19: 65-71
    CrossrefPubMedGoogle Scholar
  • 17 Pascarella S, Clément S, Guilloux K. et al. Effects of hepatitis C virus on suppressor of cytokine signaling mRNA levels: comparison between different genotypes and core protein sequence analysis. Journal of Medical Virology 2011; 83: 1005-1015
    CrossrefPubMedGoogle Scholar
  • 18 Korenaga M, Wang T, Li Y. et al. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. Journal of Biological Chemistry 2005; 280: 37481-37488
    CrossrefPubMedGoogle Scholar
  • 19 Okuda M, Li K, Beard MR. et al. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 2002; 122: 366-375
    CrossrefPubMedGoogle Scholar
  • 20 Stapleton PA, Goodwill AG, James ME. et al. Hypercholesterolemia and microvascular dysfunction: interventional strategies. Journal of Inflammation 2010; 7: 54
    CrossrefPubMedGoogle Scholar
  • 21 abd Elkawy K, El-Sisi A, Hegazy S. et al. Comparing the effects of atorvastatin and vitamin E on endothelial function of sildenafil non-responders (851.8). The FASEB Journal 2014; 28858
    PubMedGoogle Scholar
  • 22 Janicko M, Drazilova S, Pella D. et al. Pleiotropic effects of statins in the diseases of the liver. World Journal of Gastroenterology 2016; 22: 6201
    CrossrefPubMedGoogle Scholar
  • 23 Goldstein J., Brown MS. Regulation of the mevalonate pathway. Nature 1990; 343: 425-430
    CrossrefPubMedGoogle Scholar
  • 24 Peng LF, Schaefer EA, Maloof N. et al. Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A synthase. Journal of Infectious Diseases 2011; 204: 609-616
    CrossrefPubMedGoogle Scholar
  • 25 Kim SS, Peng LF, Lin W. et al. A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication. Gastroenterology 2007; 132: 311-320
    CrossrefPubMedGoogle Scholar
  • 26 Ikeda M, Abe Ki, Yamada M. et al. Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology 2006; 44: 117-125
    CrossrefPubMedGoogle Scholar
  • 27 Ye J, Wang C, Sumpter R. et al. Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation. Proceedings of the National Academy of Sciences 2003; 100: 15865-15870
    CrossrefPubMedGoogle Scholar
  • 28 Henderson LM, Patel S, Giordano TP. et al. Statin therapy and serum transaminases among a cohort of HCV-infected veterans. Digestive Diseases and Sciences 2010; 55: 190-195
    CrossrefPubMedGoogle Scholar
  • 29 Mendell J, Zahir H, Matsushima N. et al. Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. American Journal of Cardiovascular Drugs 2013; 13: 331-342
    CrossrefPubMedGoogle Scholar
  • 30 R. PP. Human experimentation. Code of ethics of the world medical association. Declaration of Helsinki. British Medical Journal 1964; 2: 177-177
    CrossrefPubMedGoogle Scholar
  • 31 Cohen J. A power primer. Psychological bulletin 1992; 112: 155-159
    CrossrefPubMedGoogle Scholar
  • 32 Abdallah OM, Abdel-Megied AM, Gouda AS. Development and validation of LC-MS/MS method for simultaneous determination of sofosbuvir and daclatasvir in human Plasma: Application to pharmacokinetic study. Biomedical Chromatography 2018; 32: e4186
    CrossrefPubMedGoogle Scholar
  • 33 Moosavi S, Borema T, Ewesuedo R. et al. PF-06881894, a proposed biosimilar to pegfilgrastim, versus US-licensed and EU-approved pegfilgrastim reference products (Neulasta): pharmacodynamics, pharmacokinetics, immunogenicity, and safety of single or multiple subcutaneous doses in healthy volunteers. Advances in Therapy 2020; 37: 3370-3391
    CrossrefPubMedGoogle Scholar
  • 34 Minami K, Higashino H, Kataoka M. et al. Species differences in the drug–drug interaction between atorvastatin and cyclosporine: In vivo study using a stable isotope-IV method in rats and dogs. European Journal of Pharmaceutical Sciences 2020; 152: 105409
    CrossrefPubMedGoogle Scholar
  • 35 Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clinical Pharmacology & Therapeutics 1975; 18: 377-390
    CrossrefPubMedGoogle Scholar
  • 36 Denning J, Cornpropst M, Flach SD. et al. Pharmacokinetics, safety, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor for HCV, following single ascending doses in healthy subjects. Antimicrobial Agents and Chemotherapy 2013; 57: 1201-1208
    CrossrefPubMedGoogle Scholar
  • 37 Goard CA, Mather RG, Vinepal B. et al. Differential interactions between statins and P-glycoprotein: Implications for exploiting statins as anticancer agents. International Journal of Cancer 2010; 127: 2936-2948
    CrossrefPubMedGoogle Scholar
  • 38 Gogman K, Peyer A, Torok M. et al. HMG-CoA reductase inhibitors and P-glycoprotein modulation. British Journal of Pharmacology 2001; 132: 1183-1192
    CrossrefPubMedGoogle Scholar
  • 39 Stage TB, Mortensen C, Khalaf S. et al. P-Glycoprotein Inhibition Exacerbates Paclitaxel Neurotoxicity in Neurons and Patients With Cancer. Clinical Pharmacology & Therapeutics 2020; 108: 671-680
    CrossrefPubMedGoogle Scholar
  • 40 Wang E-j, Casciano CN, Clement RP. et al. HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharmaceutical Research 2001; 18: 800-806
    CrossrefPubMedGoogle Scholar
  • 41 Jacobsen W, Kuhn B, Soldner A. et al. Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metabolism and Disposition 2000; 28: 1369-1378
    PubMedGoogle Scholar
  • 42 Sakaeda T, Fujino H, Komoto C. et al. Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport. Pharmaceutical Research 2006; 23: 506-512
    CrossrefPubMedGoogle Scholar
  • 43 Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clinical Pharmacokinetics 2003; 42: 1141-1160
    CrossrefPubMedGoogle Scholar
  • 44 Boyd RA, Stern RH, Stewart BH. et al. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. The Journal of Clinical Pharmacology 2000; 40: 91-98
    CrossrefPubMedGoogle Scholar
  • 45 Sharaf A, El-Shazly KA, Abd El LatifA. et al. Comparative Evaluation of the Effects of Atorvastatin and Lovastatin on the Pharmacokinetics of Aliskiren in Rats. Sains Malaysiana 2021; 50: 829-837
    CrossrefPubMedGoogle Scholar
  • 46 Abdelkawy KS, Abdelaziz RM, Abdelmageed AM. et al. Effects of green tea extract on atorvastatin pharmacokinetics in healthy volunteers. European journal of Drug Metabolism and Pharmacokinetics 2020; 45: 351-360
    CrossrefPubMedGoogle Scholar
  • 47 Sieczkowski E, Lehner C, Ambros PF. et al. Double impact on p-glycoprotein by statins enhances doxorubicin cytotoxicity in human neuroblastoma cells. International Journal of Cancer 2010; 126: 2025-2035
    PubMedGoogle Scholar
  • 48 Hong S-P, Chang K-S, Koh Y-Y. et al. Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite, norverapamil in rats: possible role of P-glycoprotein inhibition by lovastatin. Archives of Pharmacal Research 2009; 32: 1447
    CrossrefPubMedGoogle Scholar
  • 49 Martirosyan A, Clendening JW, Goard CA. et al. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance. BMC Cancer 2010; 10: 103
    CrossrefPubMedGoogle Scholar
  • 50 Hong SP, Yang JS, Han JY. et al. Effects of lovastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats: possible role of cytochrome P450 3A4 and P-glycoprotein inhibition by lovastatin. Journal of Pharmacy and Pharmacology 2011; 63: 129-135
    CrossrefPubMedGoogle Scholar
  • 51 Chung JW, Yang SH, Choi JS. Effects of lovastatin on the pharmacokinetics of nicardipine in rats. Biopharmaceutics & Drug Disposition 2010; 31: 436-441
    CrossrefPubMedGoogle Scholar
  • 52 Sanneboina S, Sammeta V, Pingili RB. et al. Influence of lovastatin on pharmacokinetics and pharmacodynamics of glipizide in healthy and streptozotocin-induced diabetic rats: involvement of P-glycoprotein inhibition. Asian J Pharm Clin Res 2016; 9: 3-8
    CrossrefPubMedGoogle Scholar
  • 53 Choi D-H, Chung J-H, Choi J-S. Pharmacokinetic interaction between oral lovastatin and verapamil in healthy subjects: role of P-glycoprotein inhibition by lovastatin. European Journal of Clinical Pharmacology 2010; 66: 285-290
    CrossrefPubMedGoogle Scholar
  • 54 King JR, Dutta S, Cohen D. et al. Drug-drug interactions between sofosbuvir and ombitasvir-paritaprevir-ritonavir with or without dasabuvir. Antimicrobial Agents and Chemotherapy 2016; 60: 855-861
    CrossrefPubMedGoogle Scholar
  • 55 Ouwerkerk-Mahadevan S, Snoeys J, Peeters M. et al. (2016) Drug–drug interactions with the NS3/4A protease inhibitor simeprevir. Clinical Pharmacokinetics 2016; 55: 197-208
    CrossrefPubMedGoogle Scholar
  • 56 Monoe C, Shimizu H, Kitaguchi K. et al. Severe Bradycardia Induced by Sofosbuvir and Amiodarone which Resolved after the Discontinuation of Both Drugs. Internal Medicine 2020; 59: 4488-4420
    CrossrefPubMedGoogle Scholar
  • 57 Hussar DA, Kavelak HL. Ledipasvir/sofosbuvir; ombitasvir/paritaprevir/ritonavir/dasabuvir sodium monohydrate; and peramivir. Journal of the American Pharmacists Association 2015; 55: 216-223
    CrossrefPubMedGoogle Scholar
  • 58 Kaur K, Gandhi MA, Slish J. Drug-drug interactions among hepatitis C virus (HCV) and human immunodeficiency virus (HIV) medications. Infectious diseases and therapy 2015; 4: 159-172
    CrossrefPubMedGoogle Scholar
  • 59 Smolders EJ, ter Horst PJ, Wolters S. et al. Cardiovascular risk management and hepatitis C: combining drugs. Clinical Pharmacokinetics 2019; 58: 565-592
    CrossrefPubMedGoogle Scholar
  • 60 Denning J, Cornpropst M, Flach SD. et al. Pharmacokinetics, Safety, and Tolerability of GS-9851, a Nucleotide Analog Polymerase Inhibitor for Hepatitis C Virus, following Single Ascending Doses in Healthy Subjects. Antimicrobial Agents and Chemotherapy 2013; 57: 1201-1208 DOI: 10.1128/aac.01262-12.
    CrossrefPubMedGoogle Scholar
  • 61 Keating GM, Vaidya A. Sofosbuvir: first global approval. Drugs 2014; 74: 273-282
    CrossrefPubMedGoogle Scholar
  • 62 HARVONI® GSH (2017) (ledipasvir and sofosbuvir) 90 mg/400 mg tablets for oral use. Summary of Product Characteristics (SmPC)
    PubMed