Tradução:

Carolina Palma
Catarina Pinheiro
Daniela Lobão
Joana C. Silva
Helena Barroso
Inês Bártolo
Patrícia Carvalho
Paula Matoso
Sheila Rocha
Victor Bezerra

Aviso Legal

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Interacções medicamentosas

Leonie Meemken e Laura Dickinson

No sentido de prever ou evitar as interacções entra fármacos é necessária uma história completa da medicação, inluíndo remédios de ervanária e drogas de uso recreativo. Em particular as combinações que envolvem inductores (p. ex. rifampicin) e inibidores (p. ex. ketoconazole) podem resultar em concentrações plasmáticas desfavoráveis dos anti-retrovirais. Por exemplo, os inibidores aumentam a concentração de alguns fármacos de tal modo que se desenvolve toxicidades e os indutores podem reduzir a tal ponto que provoquem resistências. Se não existirem dados claros sobre as interacções entre fármacos devem considerar-se hipóteses teóricas no sentido de excluir interacções farmacológicas graves. É importante olhar para os efeitos colaterais da HAART. A HAART pode influenciar a co-medicação e vice-versa. Os ajustamentos de dose da ARV e/ou da co-medicação pode ser considerada. Para mais informação veja o website www.hiv-druginteractions.org

As concentrações plasmáticas também podem ser influenciadas por vários factores tais como a idade, o sexo, doenças hepáticas e o polimorfismo genético. A dosagem individual com o uso de TDM é, muitas vezes, importante.

Fármacos particulares

Comentários: as concentrações plasmáticas de fármacos são afectados por vários factores: etnicidade, insuficiência renal ou hepática, idade, sexo. A previsão de possíveis interacções pode ser discutível e nalguns casos ser útil a monitorização terapêutica de fármacos (TDM).

Abreviaturas usadas na tabela: AUC = área sob curva, /dia, 2x/dia, 3x/dia, ¯­ = AUC redução ou aumento, TDM = monitorização terapêutica de fármacos

3TC (Lamivudina, Epivir™; em Combivir™, Trizivir™, Kivexa™)
Abacavir (ABC, Ziagen™; em Trizivir™, Kivexa™)
Atazanavir (ATV, Reyataz™)
AZT (Zidovudin, Retrovir™; também Trizivir™, Combivir™)
D4T (Estavudina, Zerit™)
Darunavir (DRV, TMC 114, PrezistaTM)
DDI (Didanosina, Videx™)
Efavirenze (EFV, Sustiva™, Stocrin™)
Emtricitabina (FTC, Emtriva™; also in of Truvada™)
Fosamprenavir (FPV, Lexiva™, Telzir™)
Indinavir (IDV, Crixivan™)
Lopinavir/r (LPV/r, Kaletra™)
Nelfinavir (NFV, Viracept™)
Nevirapina (NVP, Viramune™)
Saquinavir (SQV, Invirase 500™)
T-20 (Enfuvirtide, Fuzeon™)
Tenofovir (TDF, Viread™; component of Truvada™)
Tipranavir (TPV/r, Aptivus™)

3TC (Lamivudina, Epivir™; em Combivir™, Trizivir™, Kivexa™)

Dose aprovada: 150 mg 2x/dia ou 300 mg/dia. Eliminação: renal

Bibliografia

1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto 2006 Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com
2. US Department of Health and Human Services (DHHS) and National Institutes of Health (NIH). The living document: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Retrieved April 14, 2004. www.aidsinfo.nih.gov.

Abacavir (ABC, Ziagen™; em Trizivir™, Kivexa™)

Dose aprovada: 300 mg 2x/dia ou 600 mg/dia. Metabolizada pela via da álcool dehidrogenase e glucuronidação

* HSR = reacção de hipersensibilidade

Bibliografia

1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto 2004.
2. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com
3. McDowell JA, Chittick GE, Pilati-Stevens C, et al. Pharmacokinetic interaction of abacavir and ethanol in HIV-infected adults. Antimicrob Agents Chemother 2000 ; 44: 1686-90. http://www.amedeo.com/lit.php?id=10817729
4. Aptivus™, Boehringer Ingelheim.

Atazanavir (ATV, Reyataz™)

Dose aprovada: ATV/RTV: 300/100 mg. Metabolismo: o atazanavir (ATV) é metabolizado primariamente pelo CYP3A4 e inibe o CYP3A4, CYP2C9, CYP1A2 e a UDP-glucuronosiltransferase(UGT)-1A1 [1].

Bibliografia

1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto; 2004.
2. Kaul S, Bassi K, Damle BD, et al. Pharmacokinetic evaluation of the combination of atazanavir, enteric coated didanosine, and tenofovir disoproxil fumarate for a once daily antiretroviral regimen. Abstract A-1616, 43rd ICAAC 2003, Chicago.
3. Atazanavir. Bristol Myers-Squibb.
4. Preston S, Piliero P, O´Mara E, et al. Evaluation of steady-state interaction between atazanavir and efavirenz. Abstract 443, 9th CROI 2002, Seattle. http://63.126.3.84/2002/Abstract/13543.htm
5. Tackett D, Child M, Agarwala S, et al. Atazanavir: A summary of two pharmacokinetic drug interaction studies in healthy volunteers. Abstract 543, 10th CROI 2003, Boston.
6. Robinson BS, Riccardi KA, Gong YF, et al. BMS- 232632, a highly potent HIV protease inhibitor that can be used in in combination with other available antirtroviral agents. Antimicrob Agents Chemother 2000; 44: 2093-9. http://www.amedeo.com/lit.php?id=10898681
7. King J, Paul Lundy S, Kakuda TN et al. Pharmacokinetics of saquinavir with low-dose ritonavir or atazanavir twice daily in seronegativ volunteers. ASPIRE II. Abstract 586. 13th CROI 2006, Denver.
8. DeJesus E, Grinsztejn B, Rodriguez C, et al. Efficacy and safety of atazanavir with ritonavir or saquinavir vs lopinavir/ritonavir in patients who have experienced virologic failure on multiple HAART regimens: 48-Week results from BMS A1424-045. Abstract 54, 11th CROI 2004, San Francisco. http://www.retroconference.org/2004/cd/Abstract/547.htm
9. Boffito M, Kurowski M, Kruse G, et al. Atazanavir enhances saquinavir hard gel concentration in a ritonavir boosted once daily regimen. AIDS 2004; 18: 1292-7. http://www.amedeo.com/lit.php?id=15362661
10. Agarwala S, Russo R, Mummanemi V, et al. Steady-state pharmacokinetic interaction study of atazanavir with ritonavir in healthy subjects. Abstract H1716, 42nd ICAAC 2002, San Diego.
11. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com
12. Mummaneni V, Randall D, Chabuel D, et al. Steady–state pharnacokinetic interaction study of atazanavir with clarithromycin in healthy subjects. Abstract H1717, 42nd ICAAC 2002, San Diego.
13. Benedek ICH, Joshi A, Fiske WD, et al. Pharmacokinetic studies in healthy volunteers with efavirenz and the macrolide antibiotics, azithromycin and chlarithromycin. Abstract 347, 5th CROI 1998, Chicago.
14. Richelson E. Pharmacokinetic interactions of antidepressiva. J Clin Psychiatry 1998; 59: 22-6. http://www.amedeo.com/lit.php?id=9720479
15. Pratt CM, Mason J, Russell T. Cardiovascular safety of fexofenadine HCL. Am J Cardiol 1999; 84: 278-9. http://www.amedeo.com/lit.php?id=10444240
16. Abernethy DR, Barbey JT. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QT-prolongation. Clin Pharmacol Ther 2001; 69: 96-103. http://www.amedeo.com/lit.php?id=11240972
17. Rossi DR, Rathbun C, Slater LD. Symptomatic ortostasis with extended-release nifedipine and protease inhibitors. Ann Pharmacother 2002; 22: 1312-6. http://www.amedeo.com/lit.php?id=12389881
18. O´Mara E, Randall D, Uderman H, et al. Steady-state pharmacokinetics interaction study between BMS-232632 and ketoconazole in healthy subjects. Abstract 1646, 40th ICAAC 2000, Toronto.
19. Fichtenbaum CJ, Gerber JG, Rosenkranz S. Pharmacokinetic interaction between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002; 16: 569-77. http://www.amedeo.com/lit.php?id=11873000
20. Antoniou T, Lin-in Tseng. Interactions between recreational drugs and antiretroviral agents. Annals Pharmacother 2002; 36: 1598-613. http://www.amedeo.com/lit.php?id=12243611
21. CDC. Notice to Readers: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2004; 53:37. http://www.amedeo.com/lit.php?id=11795500
22. Lam M, Ignoffo R, Meibohm B. Ein Leitfaden für klinisch-relevante Arzneimittel-Interaktionen in der Onkologie.
23. Ghofrani HA, Olschewski H, Seeger W, et al. Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure. Pneumologie 2002; 56: 665-72. http://amedeo.com/lit.php?id=12442206
24. Alexander CS, Montaner JG, Langridge S, et al. Interaction between atazanavir/Ritonavir (ATV/r) and nevirapine (NVP) is observed in a clinical setting. Abstract P275, 7th Int Congr Drug Ther HIV Inf 2004, Glasgow.
25. Roter Hand Brief,  Bristol Myers-Squibb, December 2004
26. Kurowski M, Breske A, Kruse G, et al. Atazanavir (ATV) enhances through concentrations of nelfinavir (NFV) and its M8 metabolite in a treatment regimen without ritonavir (RTV). Abstract 90, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec.
27. Guttanti M, Raffaella de Pascalis C, Seminari E, et al. Pharmacokinetics of amprenavir given once or twice a day when combined with atazanavir in heavily pre-treated patients. AIDS 2003, 17: 2669-70. http://www.amedeo.com/lit.php?id=14685066
28. Colombo S, Buclin T, Franc C. Ritonavir-boosted atazanavir-lopinavir combination: a pharmacokinetic interaction study of total, unbound plasma and cellular exposures. Antivir Ther. 2006;11:53-62.
29. Agarwala S, Child M, Wang Y et al. Pharmacokinetic effect of famotidine on atazanavir with and without ritonavir in healthy subjects. Abstract 11, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec.
30. Wire MB et al. The pharmacokientic interaction between fosamprenavir/ritonavir and atazanavir in healthy adult subjects (APC 10018). Abstract 4.3/9. 10th EACS Conference 2005, Dublin.
31. Agarwala S, Eley T, Villegas C, et al. Pharmacokinetic interaction between tenofovir and atazanavir co-administered with ritonavir in healthy subjects. Abstract 16, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec.
32. Friedland G, Andrews L, Schreibman T et al. Lack of an effect of atazanavir on steady-state pharmcokinetics of methadone in patients chronically treated for opiate addiction. AIDS 2005; 19:1635-41. http://amedeo.com/lit.php?id=16184033
33. Sekar V, De Marez T, Spinosa-Guzman S et al. Pharmacokinetic Interaction between TMC114/RTV and Atazanavir in healthy volunteers. Abstract PE4/3.4, 10th EACS Conference 2005, Dublin.
34. Pham P, Parson T, Flexner C et al. Beneficial Pharmacokinetic Interaction between Atazanavir and Lopinavir/r. 13th CROI Denver 2006, abstract 585.
35. Vezina HE, Tschampa JM, Jennings C et al. Steady-state pharmacokinetic of lopinavir/ritonavir coadministered with atazanavir in HIV-infected subjects. Abstract 48. 7th Int Worksh Clin Pharmacol HIV Ther 2005, Lissabon.
36. Sabo JP, Elgadi M, Wruck J et al. The pharmacokinetic interaction between atazanavir/ritonavir and steady-state tipranavir/ritonavir in healthy volunteers. Abstract 41, 7th Int Worksh Clin Pharmacol HIV Ther 2005, Lissabon.

AZT (Zidovudin, Retrovir™; também Trizivir™, Combivir™)

Dose aprovada: 250 ou 300 mg 2x/dia. Metabolismo: via da glucuronidação, eliminação: renal

Bibliografia

1.         Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2006.

2.         Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com

3.         Product information: Retrovir™. Glaxo Smithkline.

4.         Polis MA, Piscitelli SC, Vogel S, et al. Chlarithromycin lowers plasma zidovudine levels in persons with HIV-infection. Antimicrob Agents Chemother 1997; 41: 1709-14. http://www.amedeo.com/lit.php?id=9257746

5.         US Department of Health and Human Services (DHHS) and National Institutes of Health (NIH). The living document: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Retrieved April 14, 2004. www.aidsinfo.nih.gov.

6.         Foscavir™. Astra Zeneca.

7.         Cooper DA, Pehrson PO, Pedersen C, et al. The efficacy and safety of zidovudine alone or as co-therapy with acyclovir for the treatment of AIDS and AIDS-related complex: a double-blind randomized trial. European-Australian Collaborative Group. AIDS 1993; 7: 197-207. http://www.amedeo.com/lit.php?id=8096703

8.         Bach MC. Possible drug interaction during therapy with azidothymidine and acyclovir for AIDS [letter]. N Engl J Med 1987; 317: 547. http://www.amedeo.com/lit.php?id=3468354

9.         Hochster H, Dieterich D, Bozzette S, et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. Ann Intern Med 1990; 113: 111-7. http://www.amedeo.com/lit.php?id=2163228

10.     Cimoch PJ, Lavelle J, Pollard R, et al. Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine and probenecid in HIV-infected subjects. JAIDS 1998; 17: 227-34. http://www.amedeo.com/lit.php?id=9495222

11.     Ruedy J, Schlechter M, Montaner JS. Zidovudine for early HIV-infection: who, when, and how? Ann Intern Med 1990; 112: 721-3.

12.     Sim SM, Higgard PG, Sales SD, et al. Effect of ribavirin on zidovudine efficacy and toxicity in vitro: a concentration-dependent interaction. AIDS Res Hum Retr 1998; 14: 1661-7.

13.     Kornhauser DM, Petty BG, Hendrix CW, et al. Probenecid and zidovudine metabolism. Lancet 1989; 2: 473-5. http://www.amedeo.com/lit.php?id=2570186

14.     Antoniou T, Lin-in Tseng. Interactions between recreational drugs and antiretroviral agents. Ann Pharmacother 2002; 36: 1598-613. http://www.amedeo.com/lit.php?id=12243611

15.      Roszko PJ, Curry K, Brazina B, et al. Standard doses of efavirenz, zidovudine, tenofovir, and didanosine may be given with tipranavir/ritonavir. Abstract 865, 2nd IAS 2003, Paris. http://www.aegis.com/conferences/2ndIASHIVPT /865.html

D4T (Estavudina, Zerit™)

Dose aprovada: 30-40 mg 2x/dia (< 60 kg: 30 mg 2x/dia). Eliminação: 34-43 % renal

Bibliografia

1.      Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2004.

2.      Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com

3.      Foisy MM, Slayter KL, Hewitt RG, et al. Pancreatitis during intravenous pentamidine therapy in an AIDS patient with prior exposure to didanosine. Ann Pharmacother 1994; 28: 1025-8. http://www.amedeo.com/lit.php?id= 7803875

4.      Landau A, Batisse D, Piketty C, et al. Lack of interference between ribavirin and nucleoside analogues in HIV/HCV co-infected individuals undergoing concomitant antiretroviral and anti-HCV combination therapy. AIDS 2000; 14: 1857-8. http://www.amedeo.com/lit.php?id=10985327

5.      Hittinger G. Mitochondrial toxicity in HIV/HCV co-infected patients treated with ribavirin, interferon alpha and antiretroviral therapy. Abstract TuPeB4516, XIV Int AIDS Conference 2002, Barcelona.

6. Smith DM, Puoti M, Sulkowski, et al. Symptomatic hyperlactatemia during a large hepatitis C treatment trial in HIV/HCV co-infected participants on stable antiretroviral therapy. Abstract MoOrB1059, XIV Int AIDS Conference 2002, Barcelona.

Darunavir (DRV, TMC 114, Prezista^TM)

Dose (aprovada nos EUA): TMC 114/r: 600/100 mg 2x/dia com alimentos [5]. Metabolismo: TMC 114 é metabolizado pelo isoenzima CYP3A4 [5]. Quando potenciado pelo, TMC 114 passa a inibidor do CYP3A4.