Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir

Clinical Pharmacokinetics

Volumn 52, Issue 11, 2013, Pages 981-994

  Cottrell, Mackenzie L ^a   Hadzic, Tanja ^a   Kashuba, Angela D M ^a  

^a UNC Hamner Institute for Drug Safety Sciences   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ABACAVIR; ALANINE AMINOTRANSFERASE; ALUMINUM MAGNESIUM HYDROXIDE; ANTACID AGENT; ANTIMYCOBACTERIAL AGENT; ANTIVIRUS AGENT; ASPARTATE AMINOTRANSFERASE; BILIRUBIN; CHOLESTEROL; CREATINE KINASE; CREATININE; CYTOCHROME P450 3A4; DOLUTEGRAVIR; EFAVIRENZ; ELVITEGRAVIR; EMTRICITABINE; ETHINYLESTRADIOL PLUS NORGESTIMATE; GLUCURONOSYLTRANSFERASE 1A1; LAMIVUDINE; METHADONE; MULTIVITAMIN; OMEPRAZOLE; ORAL CONTRACEPTIVE AGENT; ORGANIC CATION TRANSPORTER 2; PHOSPHORUS; RALTEGRAVIR; RIFAMPICIN; TENOFOVIR DISOPROXIL; TRIACYLGLYCEROL LIPASE; UNINDEXED DRUG;

ABNORMAL DREAMING; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANTIVIRAL ACTIVITY; ANXIETY DISORDER; APHASIA; AREA UNDER THE CURVE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; ASTHENIA; BILIRUBIN BLOOD LEVEL; BRONCHITIS; CENTRAL NERVOUS SYSTEM DISEASE; CEREBROVASCULAR ACCIDENT; CHOLESTEROL BLOOD LEVEL; CONVULSION; COUGHING; CREATINE KINASE BLOOD LEVEL; CREATININE BLOOD LEVEL; DEPRESSION; DIARRHEA; DIZZINESS; DRUG BLOOD LEVEL; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG EXPOSURE; DRUG HALF LIFE; DRUG HYPERSENSITIVITY; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG TOLERABILITY; DRUG TRANSPORT; DRUG WITHDRAWAL; DYSPEPSIA; FATIGUE; FEVER; GASTROINTESTINAL SYMPTOM; GLOMERULUS FILTRATION RATE; HEADACHE; HEART ARRHYTHMIA; HEMATOMA; HEPATITIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IN VITRO STUDY; INSOMNIA; KIDNEY FAILURE; MENTAL DISEASE; NAUSEA; NEUTROPHIL COUNT; NOSE OBSTRUCTION; PHARYNGITIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPE; PHOSPHATE BLOOD LEVEL; PRIORITY JOURNAL; PROTHROMBIN TIME; QT PROLONGATION; RASH; REVIEW; RHINOPHARYNGITIS; SIDE EFFECT; SLEEP DISORDER; SUICIDE ATTEMPT; TRIACYLGLYCEROL LIPASE BLOOD LEVEL; UPPER RESPIRATORY TRACT INFECTION; VIRUS INHIBITION; VIRUS MUTATION;

DRUG INTERACTIONS; HETEROCYCLIC COMPOUNDS, 3-RING; HIV INTEGRASE INHIBITORS; HUMANS;

EID: 84886772513     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.1007/s40262-013-0093-2     Document Type: Review

References (57)

1. Adams JL, Greener BN, Kashuba AD. Pharmacology of HIV integrase inhibitors. Curr Opin HIV AIDS. 2012;7(5):390-400.
2. Dejesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137) (abstract no. TUPEB032 plus poster). In: 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 22-25 Jul 2007, Sydney.
3. Hazuda DJ, Miller MD, Nguyen BY, et al. Resistance to the HIV-integrase inhibitor raltegravir: analysis of protocol 005, a phase 2 study in patients with triple-class resistant HIV-1 infection (abstract no. 8). In: 16th International HIV Drug Resistance Workshop, 12-16 Jun 2007, Barbados.
4. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a phase 2 study of elvitegravir (GS-9137) (abstract no. 9). In: 16th International HIV Drug Resistance Workshop, 12-16 Jun 2007, Barbados.
5. Garrido C, Villacian J, Zahonero N, et al. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother. 2012;56(6):2873-8.
6. Hare S, Smith SJ, Metifiot M, et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011;80(4):565-72.
7. Kobayashi M, Yoshinaga T, Seki T, et al. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011;55(2):813-21.
8. Hightower KE, Wang R, Deanda F, et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother. 2011;55(10):4552-9.
9. Underwood MR, Johns BA, Sato A, et al. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr. 2012;61(3):297-301.
10. Canducci F, Ceresola ER, Boeri E, et al. Cross-resistance profile of the novel integrase inhibitor dolutegravir (S/GSK1349572) using clonal viral variants selected in patients failing raltegravir. J Infect Dis. 2011;204(11):1811-5.
11. Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010;54(1):254-8.
12. Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011;25(14):1737-45.
13. Song I, Borland J, Savina PM, et al. Pharmacokinetics of dolutegravir in subjects with moderate hepatic impairment (abstract no. N-121 plus poster). In: 19th Conference on Retrovirus and Opportunistic Infections, 5-8 Mar 2012, Seattle.
14. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006;43(1):1-5.
15. Reese MJ, Savina PM, Generaux GT, et al. In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos. 2013;41(2):353-61.
16. Song I, Borland J, Chen S, et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012;56(3):1627-9.
17. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12(2):111-8.
18. Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING study. J Infect Dis. 2013;207:740-8.
19. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381(9868):735-43.
20. Letendre S, Mills A, Tashima K, et al. Distribution and antiviral activity in cerebrospinal fluid (CSF) of the integrase inhibitor, dolutegravir (DTG): ING116070 week 16 results (abstract no. 178LB plus poster). In: 20th Conference on Retroviruses and Opportunistic Infections, 3-6 Mar 2013, Atlanta.
21. Greener BN, Adams JL, Patterson KB, et al. Single and multiple dose dolutegravir pharmacokinetics in the genital tract and colorectum of HIV negative men and women (abstract no. 531 plus poster). In: 20th Conference on Retroviruses and Opportunistic Infections, 3-6 Mar 2013, Atlanta.
22. Patterson KB, Prince HMA, Wang R, et al. Pharmacokinetics (PK) of raltegravir (RAL) in the blood plasma (BP) and genital tract (GT) in HIV+ and HIV- women (abstract no. O-17 plus poster). In: 5th Annual HIV Transmission Workshop, 15-16 Jul 2010, Vienna.
23. Dumond JB, Patterson KB, Pecha AL, et al. Maraviroc concentrates in the cervicovaginal fluid and vaginal tissue of HIV-negative women. J Acquir Immune Defic Syndr. 2009;51(5):546-53.
24. Salas Herrera IG, Pearson RM, Turner P. Quantitation of albumin and alpha-1-acid glycoprotein in human cervical mucus. Hum Exp Toxicol. 1991;10(2):137-9.
25. Antoniou T, Hasan S, Loutfy MR, et al. Pharmacokinetics of maraviroc, raltegravir, darunavir, and etravirine in the semen of HIV-infected men. J Acquir Immune Defic Syndr. 2013;62(2):e58-60.
26. Calcagno A, Bonora S, D'Avolio A, et al. Raltegravir penetration in seminal plasma of healthy volunteers. Antimicrob Agents Chemother. 2010;54(6):2744-5.
27. Cao YJ, Hendrix CW. Male genital tract pharmacology: developments in quantitative methods to better understand a complex peripheral compartment. Clin Pharmacol Ther. 2008;83(3):401-12.
28. Viiv Healthcare (2012). Dolutegravir Renal Impairment Study. In: US National Institutes of Health. ClinicalTrials.gov (online). http://clinicaltrials.gov/ct2/show/NCT01353716. Accessed 26 Feb 2013.
29. GlaxoSmithKline. A phase I, open-label, parallel-group study to evaluate the pharmacokinetics and safety of dolutegravir in subjects with renal impairment and healthy matched control subjects (ING113125). In: Results summary for 113125, GlaxoSmithKline. http://www.gsk-clinicalstudyregister.com/result-detail.jsp?protocolId=113125&studyId=F847E25C-9F8F-494E-82AA-DCB140DE7892&compound=dolutegravir&type=Compound&letterrange=A-F. Accessed 17 May 2013.
30. National Institute of Allergy and Infectious Diseases (2013). Safety of and immune response to GSK1349572 in HIV-1 infected infants, children, and adolescents. In: US National Institutes of Health. ClinicalTrials.gov (online). http://clinicaltrials.gov/ct2/show/NCT01302847?term=NCT01302847&rank=1. Accessed 27 Feb 2013.
31. Hazra R, Viani R, Acosta E, et al. Pharmacokinetics, safety and efficacy of dolutegravir (DTG; S/GSK1349572) in HIV-1-positive adolescents: preliminary analysis from IMPAACT P1093 (abstract no. TUAB0203). In: 19th International AIDS Conference, 22-27 Jul 2012, Washington DC.
32. Song I, Shuguang C, Lou Y et al. Pharmacokinetic (PK) and pharmacodynamic (PD) relationship of GSK1349572, a next generation integrase inhibitor (INI), in HIV-1 (abstract no. WEPEB250 plus poster). In: IAS 2009-5th Conference on HIV Pathogenesis, Treatment and Prevention; 19-22 Jul 2009, Cape Town.
33. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results - SINGLE (ING114467) (abstract no. H556b and oral presentation). In: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, 9-12 Sep 2012; San Francisco.
34. Brinson C, Walmsley SL, Keikawaus A, et al. Dolutegravir treatment response and safety by key subgroups in treatment naive HIV infected individuals (abstract no. 554 plus poster). In: 20th Conference on Retroviruses and Opportunistic Infections, 3-6 Mar 2013, Atlanta.
35. Nichols G, Mills A, Grossberg R, et al. Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor-based regimen: week 24 phase 3 results from VIKING-3. J Int AIDS Soc. 2012;15(Suppl 4):18112.
36. Pozniak A, Mingrone H, Shuldyakov A, et al. Dolutegravir (DTG) versus raltegravir (RAL) in ART-experienced, integrase-naive subjects: 24-week interim results from SAILING (ING111762) (abstract no. 179LB plus poster). In: 20th Conference on Retroviruses and Opportunistic Infections, 3-6 Mar 2013, Atlanta.
37. van Luin M, Kuks PF, Burger DM. Use of therapeutic drug monitoring in HIV disease. Curr Opin HIV AIDS. 2008;3(3):266-71.
38. Koteff J, Borland J, Chen S, et al. A phase 1 study to evaluate dolutegravir's effect on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol. 2013;75(4):990-6.
39. Chen S, Min SS, Peppercorn A, et al. Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization. Pharmacotherapy. 2012;32(4):333-9.
40. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov.libproxy.lib.unc.edu/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 2 March 2013.
41. Song I, Min SS, Borland J, et al. Lack of interaction between the HIV integrase inhibitor S/GSK1349572 and tenofovir in healthy subjects. J Acquir Immune Defic Syndr. 2010;55(3):365-7.
42. Ward B, Gorski C, Jones D, et al. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: Implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Therap. 2003;306(1):287-300.
43. Song I, Borland J, Lou Y, et al. Effects of enzyme inducers, tipranavir and efavirenz, on the pharmacokinetics of the integrase inhibitor, dolutegravir (S/GSK1349572) (abstract no. O-02 plus oral presentation). In: 12th International Workshop on Clinical Pharmacology of HIV therapy, 13-15 Apr 2011, Miami.
44. Mascolini M. No dolutegravir (GSK572, integrase) dose adjustment needed with efavirenz or tipranavir/ritonavir (abstract no. 1111). In: 12th International Workshop on Clinical Pharmacology of HIV Therapy, 13-15 Apr 2011, Miami.
45. Ford SL, Gould E, Chen S, et al. Lack of pharmacokinetic (PK) interaction between rilpivirine and the integrase inhibitors dolutegravir and S/GSK1265744. In: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 9-12 Sep 2012, San Francisco.
46. Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Clinical perspective on antiretroviral drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Antivir Ther. 2010;15(6):817-29.
47. Song I, Borland J, Min S, et al. Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother. 2011;55(7):3517-21.
48. Song I, Borland J, Chen S, et al. Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br J Clin Pharmacol. 2011;72(1):103-8.
49. Song I, Min SS, Borland J, et al. The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants. J Clin Pharmacol. 2011;51(2):237-42.
50. King JR, Acosta EP. Tipranavir: a novel nonpeptidic protease inhibitor of HIV. Clin Pharmacokinet. 2006;45(7):665-82.
51. Song I, Borland J, Chen S, et al. Effect of fosamprenavir/ritonavir on the pharmacokinetics of the integrase inhibitor, dolutegravir, in healthy subjects (abstract no. A1-1727). In: 51st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, 17-20 Sep 2011, Chicago.
52. Patel P, Song I, Borland J, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother. 2011;66(7):1567-72.
53. Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013;62(1):21-7.
54. Song I, Mark S, Borland J, et al. Dolutegravir has no effect on the pharmacokinetics of methadone or oral contraceptives with norgestimate and ethinyl estradiol (abstract no. 535 plus poster). In: 20th Conference on Retroviruses and Opportunistic Infections, 3-6 Mar 2013, Atlanta.
55. Johnson M, Borland J, Shuguang C, et. al. The effect of boceprevir and telaprevir on dolutegravir pharmacokinetics, in healthy adult subjects (abstract no. 016). In: 14th International Workshop on Clinical Pharmacology of HIV Therapy, 22-14 Apr 2013, Amsterdam.
56. Tolson AH, Li H, Eddington ND, et al. Methadone induces the expression of hepatic drug-metabolizing enzymes through the activation of pregnane X receptor and constitutive androstane receptor. Drug Metab Dispos. 2009;37(9):1887-94.
57. AIDSinfo Drug Database. 2013. http://aidsinfo.nih.gov/drugs/509/dolutegravir/0/patient/. Accessed 16 March 2013.