Implications of gender and pregnancy for antiretroviral drug dosing

Current Opinion in HIV and AIDS

Volumn 3, Issue 3, 2008, Pages 277-282

  Best, Brookie M ^a,b   Capparelli, Edmund V ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b MC 0719 ^*  (United States)

Author keywords

Antiretroviral; Gender; Pharmacology; Pregnancy

Indexed keywords

ABACAVIR; ANTIRETROVIRUS AGENT; ATAZANAVIR; CYTOCHROME P450 3A; DELAVIRDINE; DIDANOSINE; EFAVIRENZ; EMTRICITABINE; INDINAVIR; LAMIVUDINE; LOPINAVIR; LOPINAVIR PLUS RITONAVIR; NELFINAVIR; NEVIRAPINE; PROTEINASE INHIBITOR; RITONAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; SAQUINAVIR; STAVUDINE; TENOFOVIR; ZIDOVUDINE;

AREA UNDER THE CURVE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DISPOSITION; DRUG EXCRETION; DRUG EXPOSURE; DRUG METABOLISM; DRUG PROTEIN BINDING; GENDER; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; PREGNANCY; PRIORITY JOURNAL; PROGESTERONE BLOOD LEVEL; REVIEW; TREATMENT RESPONSE;

EID: 42049088302     PISSN: 1746630X     EISSN: 17466318     Source Type: Journal    
DOI: 10.1097/COH.0b013e3282f39f7e     Document Type: Review

References (73)

1. AIDS epidemic update. December 2006 [online]. http://data.unaids.org/pub/ EpiReport/2006/02-Global_Summary_2006_EpiUpdate_eng.pdf. [Accessed 3 October 2007]. This annual report provides current estimates for the global HIV/AIDS epidemic overall, and by many different regions and subgroups.
2. Greenblatt DJ, Abernethy DR, Locniskar A, et al. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984; 61:27-35.
3. Cummins CL, Wu CY, Benet LZ. Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P-glycoprotein. Clin Pharmacol Ther 2002; 72:474-489.
4. Kang D, Verotta D, Krecic-Shepard ME, Modi NB, et al. Population analyses of sustained-release verapamil in patients: effects of sex, race, and smoking. Clin Pharmacol Ther 2003; 73:31-40.
5. Krecic-Shepard ME, Barnas CR, Slimko J, et al. Gender-specific effects on verapamil pharmacokinetics and pharmacodynamics in humans. J Clin Pharmacol 2000; 40:219-230.
6. Mould DR, Zhang X, Nieforth K, et al. Population pharmacokinetics and exposure-response relationship of enfuvirtide in treatment-experienced human immunodeficiency virus type 1-infected patients. Clin Pharmacol Ther 2005; 77:515-528.
7. Burger D, van der Heiden I, la Porte C, et al. Interpatient variability in the pharmacokinetics of the HIV nonnucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol 2006; 61:148-154.
8. Kappelhoff BS, Huitema AD, Sankatsing SU, et al. Population pharmacokinetics of indinavir alone and in combination with ritonavir in HIV-1-infected patients. Br J Clin Pharmacol 2005; 60:276-286.
9. Jullien V, Urien S, Hirt D, et al. Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years. Antimicrob Agents Chemother 2006; 50:3548-3555.
10. Kappelhoff BS, van Leth F, MacGregor TR, et al. Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study. Antivir Ther 2005; 10:145-155.
11. Fletcher CV, Jiang H, Brundage RC, et al. Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical Trials Group Study 359. J Infect Dis 2004; 189:1176-1184.
12. Gatti G, Di Biagio A, Casazza R, et al. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS 1999; 13:2083-2089.
13. Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS 2003; 17:2159-2168.
14. Morgan DJ. Drug disposition in mother and fetus. Clin Exp Pharmacol Physiol 1997; 24:869-873.
15. Loebstein R, Lalkin A, Koren G. Pharmacokinetic changes during pregnancy and their clinical relevance. Clin Pharmacokinet 1997; 33:328-343.
16. Krauer B, Krauer F, Hytten FE. Drug disposition and pharmacokinetics in the maternal-placental-fetal unit. Pharmacol Ther 1980; 10:301-328.
17. Krauer B, Dayer P, Anner R. Changes in serum albumin and "1-acid glycoprotein concentrations during pregnancy: An analysis of fetal-maternal pairs". Br J Obstet Gynecol 1984; 91:875-881.
18. Dean M, Stock B, Patterson RJ, Levy G. Serum protein binding of drugs during and after pregnancy in humans. Clin Pharmacol Ther 1980; 28:253-261.
19. Wadelius M, Darj E, Frenne G, Rane A. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther 1997; 62:400-407.
20. Davis M, Simmons CJ, Dordoni B, et al. Induction of hepatic enzymes during normal human pregnancy. J Obstet Gynaecol Br Commonw 1973; 80:690-694.
21. Little BB. Pharmacokinetics during pregnancy: evidence-based maternal dose formulation. Obstet Gynecol 1999; 93 (5 Pt 2):858-868.
22. Sandberg JA, Slikker W. Developmental pharmacology and toxicology of anti-HIV therapeutic agents: dideoxynucleosides. FASEB J 1995; 9:1157-1163.
23. Stein DS, Moore KH. Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians. Pharmacotherapy 2001; 21:11-34.
24. Best BM, Mirochnick M, Capparelli EV, et al. Impact of pregnancy on abacavir pharmacokinetics. AIDS 2006; 20:553-560.
25. Chappuy H, Treluyer JM, Jullien V, et al. Maternal-fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother 2004; 48:4332-4336.
26. Wang Y, Livingston E, Patil S, et al. Pharmacokinetics of didanosine in antepartum and postpartum human immunodeficiency virus-infected pregnant women and their neonates: an AIDS clinical trials group study. J Infect Dis 1999; 180:1536-1541.
27. Pereira CM, Nosbisch C, Winter HR, et al. Transplacental pharmacokinetics of dideoxyinosine in pigtailed macaques. Antimicrob Agents Chemother 1994; 38:781-786.
28. Tuntland T, Odinecs A, Pereira CM, et al. In vitro models to predict the in vivo mechanism, rate, and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus. Am J Obstet Gynecol 1999; 180 (1 Pt 1):198-206.
29. Bawdon RE. The ex vivo human placental transfer of the anti-HIV nucleoside inhibitor abacavir and the protease inhibitor amprenavir. Infect Dis Obstet Gynecol 1998; 1998:244-246.
30. Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis 1998; 178:1327-1333.
31. Bloom SL, Dias KM, Bawdon RE, Gilstrap LC. The maternal-fetal transfer of lamivudine in the ex vivo human placenta. Am J Obstet Gynecol 1997; 176:291-293.
32. Mandelbrot L, Peytavin G, Firtion G, Farinotti R. Maternal-fetal transfer and amniotic fluid accumulation of lamivudine in human immunodeficiency virus-infected pregnant women. Am J Obstet Gynecol 2001; 184:153-158.
33. Wade NA, Unadkat JD, Huang S, et al. Pharmacokinetics and safety of stavudine in HIV-infected pregnant women and their infants: Pediatric AIDS Clinical Trials Group protocol 332. J Infect Dis 2004; 190:2167-2174.
34. Burchett S, Best B, Mirochnick M, et al. Tenofovir pharmacokinetics during pregnancy, at delivery and postpartum. Poster presentation at 14th Conference on Retroviruses and Opportunistic Infections; 25-28 February 2007; Los Angeles. Abstract 738b. This preliminary report describes significantly decreased tenofovir pharmacokinetics during the third trimester compared to the same women postpartum. The small magnitude of AUC difference, however, suggests that standard tenofovir doses will be sufficient for most women in pregnancy.
35. Bonora S, Gonzalez de Requena D, et al. Transplacental Passage of Tenofovir and other Antiretrovirals at Delivery. Poster presentation at 14th Conference on Retroviruses and Opportunistic Infections; 25-28 February 2007; Los Angeles. Abstract 738a. This study described placental transport of tenofovir, showing approximately equal amounts in cord blood and maternal plasma, but with large variation between subjects.
36. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994; 331:1173-1180.
37. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 2002; 29:484-494.
38. Watts DH, Brown ZA, Tartaglione T, et al. Pharmacokinetic disposition of zidovudine during pregnancy. J Infect Dis 1991; 163:226-232.
39. Sperling RS, Roboz J, Dische R, et al. Zidovudine pharmacokinetics during pregnancy. Am J Perinatol 1992; 9:247-249.
40. O'Sullivan MJ, Boyer PJ, Scott GB, et al. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Zidovudine Collaborative Working Group. Am J Obstet Gynecol 1993; 168:1510-1516.
41. Pons JC, Taburet AM, Singlas E, et al. Placental passage of azathiothymidine (ZDV) during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound. Eur J Obstet Gynecol Reprod Biol 1991; 40:229-231.
42. Hirsch MS, Brun-Vezinet F, D'Aquila RT, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel. JAMA 2000; 283:2417-2426.
43. Taylor GP, Lyall EG, Back D, et al. Pharmacological implications of lengthened in-utero exposure to nevirapine. Lancet 2000; 355:2134-2135.
44. Capparelli E, Aweeka F, Best B, et al. Effect of pregnancy on nevirapine pharmacokinetics during chronic therapy. Poster presentation at 6th International Workshop on Clinical Pharmacology of HIV Therapy; 28-30 April 2005; Quebec.
45. Gingelmaier A, Kurowski M, Kastner R, et al. Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery. AIDS 2006; 20:1737-1743.
46. Mirochnick M, Siminski S, Fenton T, et al. Nevirapine pharmacokinetics in pregnant women and in their infants after in utero exposure. Pediatr Infect Dis J 2001; 20:803-805.
47. Cheeseman SH, Havlir D, McLaughlin MM, et al. Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8:141-151.
48. Mirochnick M, Fenton T, Gagnier P, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team. J Infect Dis 1998; 178:368-374.
49. Musoke P, Guay LA, Bagenda D, et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS 1999; 13:479-486.
50. Mirochnick M, Clarke DF, Dorenbaum A. Nevirapine: pharmacokinetic considerations in children and pregnant women. Clin Pharmacokinet 2000; 39:281-293.
51. Bristol-Myers Squibb. Company DP. Sustiva package insert. Princeton, NJ, Jan 2007.
52. Public Health Service Task Force. Safety and Toxicity of Individual Antiretroviral Agents in Pregnancy [online]. http://www.aidsinfo.nih.gov/ guidelines/perinatal/ST_052303.pdf. [Accessed 3 October 2007].
53. Fundaro C, Genovese O, Rendeli C, et al. Myelomeningocele in a child with intrauterine exposure to efavirenz. AIDS 2002; 16:299-300.
54. Barry M, Gibbons S, Back D, Mulcahy F. Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations. Clin Pharmacokinet 1997; 32:194-209.
55. Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in utero exposure. Pediatr Infect Dis J 2002; 21:835-838.
56. Marzolini C, Rudin C, Decosterd LA, et al. Transplacental passage of protease inhibitors at delivery. AIDS 2002; 16:889-893.
57. Hirt D, Urien S, Jullien V, et al. Pharmacokinetic modelling of the placental transfer of nelfinavir and its M8 metabolite: a population study using 75 maternal-cord plasma samples. Br J Clin Pharmacol 2007; 64:634-644. This study evaluated nelfinavir and its active metabolite concentrations in maternal plasma, cord blood and amniotic fluid, finding that fetal exposure to nelfinavir is approximately 25% of maternal exposure, and will be unlikely to protect the fetus from vertical HIV-1 transmission.
58. Sudhakaran S, Rayner CR, Li J, et al. Differential protein binding of indinavir and saquinavir in matched maternal and umbilical cord plasma. Br J Clin Pharmacol 2007; 63:315-321. This study described a potential mechanism to explain the poor penetration of protease inhibitors across the placenta. Unbound fractions of saquinavir and indinavir were different in maternal and cord blood paired samples, driven by differential alpha-1 acid glycoprotein concentrations.
59. Ripamonti D, Cattaneo D, Airoldi M, et al. Atazanavir-based HAART in Pregnancy. Poster presentation at 14th Conference on Retroviruses and Opportunistic Infections; 25-28 February 2007; Los Angeles. Abstract 742. This is the only report of atazanavir pharmacokinetics in pregnant women, and these preliminary results suggest that ritonavir-boosted atazanavir may be given at standard doses to pregnant women.
60. Hayashi S, Beckerman K, Homma M, et al. Pharmacokinetics of indinavir in HIV-positive pregnant women. AIDS 2000; 14:1061-1062.
61. Unadkat JD, Wara DW, Hughes MD, et al. Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother 2007; 51:783-786. This intensive pharmacokinetic study demonstrated that indinavir AUC was 68% lower during pregnancy compared to postpartum using 800 mg three times daily, and that indinavir should not be used at this dose in pregnancy.
62. Stek AM, Mirochnick M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy. AIDS 2006; 20:1931-1939.
63. Manavi K, McDonald A, Al-Sharqui A. Plasma lopinavir trough levels in a group of pregnant women on lopinavir, ritonavir, zidovudine, and lamivudine. AIDS 2007; 21:643-645. This study described decreased low plasma lopinavir trough concentrations via therapeutic drug monitoring of 26 women on lopinavir during pregnancy.
64. Mirochnick M, Stek A, Capparelli E, et al. Adequate lopinavir exposure achieved with a higher dose during the 3rd trimester of pregnancy. Poster presentation at 13th Conference on Retroviruses and Opportunistic Infections; 5-8 February 2006; Denver. Abstract 710.
65. Bryson YJ, Stek A, Mirochnick M, et al. PACTG 353: A phase I study of safety, pharmacokinetics and antiviral activity of combination nelfinavir (NFV), ZDV and 3TC in HIV infected pregnant women and their infants. Poster presentation at 7th Conference on Retroviruses and Opportunistic Infections; 2 February 2000; San Francisco. Abstract 715.
66. Bryson YJ, Stek A, Mirochnick M, et al. Pharmacokinetics, antiviral activity and safety of nelfinavir (NFV) with ZDV/3TC in pregnant HIV-infected women and their infants: PACTG 353 Cohort 2. Poster presentation at 9th Conference on Retroviruses and Opportunistic Infections; February 2002; Seattle. Abstract 759-W.
67. Mirochnick M, Bryson Y, Stek A, et al. Pharmacokinetics (PK) of Nelfinavir (NFV) and its M8 Metabolite in Pregnant HIV-Infected Women and Their Infants: PACTG 353. Poster presentation at Pediatric Academic Societies Meeting; May 2003; Seattle. Abstract 1891.
68. Read JS, Best B, Stek A, et al. Nelfinavir pharmacokinetics (625mg tablets) during the third trimester of pregnancy and postpartum. Poster presentation at 14th Conference on Retroviruses and Opportunistic Infections; 25-28 February 2007; Los Angeles. Abstract 740. This preliminary report of 27 women taking the new formulation of nelfinavir showed highly variable and significantly lower nelfinavir exposure during pregnancy compared to postpartum. Nearly all subjects were below suggested trough concentrations, suggesting higher nelfinavir doses, or therapeutic drug monitoring should be considered for all pregnant women taking nelfinavir.
69. Villani P, Floridia M, Pirillo MF, et al. Pharmacokinetics of nelfinavir in HIV-1-infected pregnant and nonpregnant women. Br J Clin Pharmacol 2006; 62:309-315.
70. Acosta EP, Zorrilla C, Van Dyke R, et al. Pharmacokinetics of saquinavir-SGC in HIV-infected pregnant women. HIV Clin Trials 2001; 2:460-465.
71. Vithayasai V, Moyle GJ, Supajatura V, et al. Safety and efficacy of saquinavir soft-gelatin capsules+zidovudine+optional lamivudine in pregnancy and prevention of vertical HIV transmission. J Acquir Immune Defic Syndr 2002; 30:410-412.
72. Acosta EP, Bardeguez A, Zorrilla CD, et al. Pharmacokinetics of saquinavir plus low-dose ritonavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother 2004; 48:430-436.
73. Lopez-Cortes LF, Ruiz-Valderas R, Rivero A, et al. Efficacy of low-dose boosted saquinavir once daily plus nucleoside reverse transcriptase inhibitors in pregnant HIV-1-infected women with a therapeutic drug monitoring strategy. Ther Drug Monit 2007; 29:171-176. This is the first report of once-daily, ritonavir-boosted saquinavir use during pregnancy, and showed that over 90% of women achieved target saquinavir minimum concentrations, while three subjects required upward dose titration.