The concurrent use of zidovudine and ganciclovir produces a verymarked increase in haematological toxicity,without any apparentincrease in efficacy. Didanosine serum levels are raised by ganciclovir, but there is some evidence suggesting that efficacy ofganciclovir prophylaxis is reduced. Ganciclovir does not appearto interact with stavudine,and there is no clinically importantpharmacokinetic interaction between ganciclovir and zalcitabine.Until further information is available, manufacturers of lamivudine advise avoidance of intravenous ganciclovir.
Buffered didanosine 200mg twice daily was given to 12 HIV-positive patients with oral ganciclovir 1 g three times daily. When didanosine was given 2 hrs before ganciclovir, maximum serum levels and AUC of didanosine were raised by about 47 % and 83%, respectively, and those of ganciclovir were decreased by about 26 % and 22%, respectively. When didanosine was given simultaneously with ganciclovir, maximum serum levels and AUC of didanosine were similarly raised, by about 53 % and 77%, respectively, but those of ganciclovir were unchanged. The renal clearance of didanosine was not significantly changed by ganciclovir (See reference number 1). Similar increases in didanosine levels with ganciclovir given intravenously(See reference number 2) and high-dose oral ganciclovir 2 g every 8 hrs have also been reported (See reference number 3). However, in contrast, an earlier study found that pharmacokinetics of didanosine (sachet preparation) were not altered by intravenous ganciclovir (See reference number 4).
Rates of dose-limiting intolerance to combination of didanosine and ganciclovir were reported to be similar to those seen with didanosine alone in one small study (15 of 32 patients tolerated usual doses of didanosine with ganciclovir) (See reference number 5). Analysis of results of a large randomised study unexpectedly suggested that there was an increased risk of cytomegalovirus infection in those patients taking ganciclovir and didanosine, when compared with those not taking didanosine (See reference number 6).
In a study of 11 HIV-positive patients, oral ganciclovir 1 g three times daily had no significant effect on pharmacokinetics of stavudine 40mg twice daily, nor were pharmacokinetics of ganciclovir affected by stavudine (See reference number 8). There were no serious or severe adverse events attributed to combination.
In a study in 10 HIV-positive patients, zalcitabine 750 micrograms every 8 hrs increased AUC of oral ganciclovir 1 g three times daily by 22%. There was no change in zalcitabine pharmacokinetics. There were no serious or severe adverse events attributed to combination (See reference number 8).
The efficacy of zidovudine 100 or 200mg every 4 hours, given alone or with intravenous ganciclovir 5 mg/kg twice daily for 14 days, then once daily for 5 days of each week, was assessed in 40 patients for treatment of cytomegalovirus (CMV). Severe haematological toxicity occurred in all of first 10 patients given zidovudine 1.2 g daily and ganciclovir. Consequently dose of zidovudine was reduced to 600mg daily. Overall 82 % of 40 patients enrolled experienced profound and rapid toxicity (anaemia, neutropenia, leucopenia, gastrointestinal disturbances). Zidovudine dosage reductions to 300mg daily were needed in many patients. No change in pharmacokinetics of zidovudine or ganciclovir was noted (See reference number 9).
Increased toxicity (myelotoxicity and pancytopenia) following use of both drugs has also been reported elsewhere (See reference number 11,12)
In contrast to first study,(See reference number 9) a specific study on pharmacokinetics of zidovudine and ganciclovir in HIV-positive subjects reported that oral ganciclovir increased maximum levels and AUC of zidovudine by 38 % and 15%, respectively, without altering renal clearance. Zidovudine did not alter ganciclovir pharmacokinetics (See reference number 1).
It is not known why ganciclovir increases levels of didanosine and zidovudine: it does not appear to be due to competition for active secretion by kidney tubules (See reference number 1)
The toxicity of zidovudine/ganciclovir combination may be simply additive,(See reference number 9) but in vitro studies with three human cell lines found synergistic cytotoxicity when both drugs were used (See reference number 13)
There is some in vitro evidence to suggest that ganciclovir antagonises anti-HIV activity of zidovudine and didanosine (See reference number 14)
The interactions between ganciclovir and didanosine or zidovudine would appear to be established, but clinical importance is uncertain. Zidovudine seems to be associated with greater toxicity than didanosine. However, there is also some evidence suggesting reduced ganciclovir efficacy in presence of didanosine, and this requires further study. Close and careful monitoring is required if either combination is used.
Ganciclovir does not appear to alter pharmacokinetics of stavudine or zalcitabine. Zalcitabine increased ganciclovir levels to a minor extent,although this is probably not clinically important.
1.
Cimoch PJ,Lavelle J, Pollard R, Griffy KG, Wong R, Tarnowski TL, Casserella S, Jung D.Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine,and probenecid in HIV-infected subjects. J Acquir Immune Defic Syndr Hum Retrovirol (1998) 17, 227–34.
2.
Frascino RJ,Anderson RD, Griffy KG, Jung D, Yu S. Two multiple dose crossover studiesof IV ganciclovir (GCV) and didanosine (ddI) in HIV infected persons. Intersci Conf Antimicrob Agents Chemother (1995) 35, 6.
3.
Jung D,Griffy K, Dorr A, Raschke R, Tarnowski TL, Hulse J, Kates RE. Effect of high-doseoral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positivepatients. J Clin Pharmacol (1998) 38, 1057–62.
4.
Hartman NR,Yarchoan R, Pluda JM, Thomas RV, Wyvill KM, Flora KP, Broder S, JohnsDG. Pharmacokinetics of 2:6.6pt; font-weight:normal; color:#000000″>′,3:6.6pt; font-weight:normal; color:#000000″>′-dideoxyinosine in patients with severe human immunodeficiency infection. II. The effects of different oral formulations and the presence of other medications. Clin Pharmacol Ther (1991) 50, 278–85.
5.
Jacobson MA,Owen W, Campbell J, Brosgart C, Abrams DI. Tolerability of combined ganciclovir and didanosine for the treatment of cytomegalovirus disease associated with AIDS.Clin Infect Dis (1993) 16 (Suppl 1), S69–S73.
6.
Brosgart CL,Louis TA, Hillman DW, Craig CP, Alston B, Fisher E, Abrams DI, Luskin-Hawk RL, Sampson JH, Ward DJ, Thompson MA, Torres RA. A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirusdisease in HIV-infected individuals. AIDS (1998) 12, 269–77.
7.
Epivir (Lamivudine). GlaxoSmithKline UK. UK Summary of product characteristics,March2007.
8.
Jung D,AbdelHameed MH, Teitelbaum P, Dorr A, Griffy K. The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV-and CMV-seropositive patients. J Clin Pharmacol (1999) 39, 505–12.
9.
Hochster H,Dieterich D, Bozzette S, Reichman RC, Connor JD, Liebes L, Sonke RL, SpectorSA, Valentine F, Pettinelli C, Richman DD. Toxicity of combined ganciclovir and zidovudinefor cytomegalovirus disease associated with AIDS. An AIDS clinical trials group study. Ann Intern Med (1990) 113, 111–17.
Millar AB,Miller RF, Patou G, Mindel A, Marsh R, Semple SJG. Treatment of cytomegalovirus retinitis with zidovudine and ganciclovir in patients with AIDS: outcome and toxicity.Genitourin Med (1990) 66, 156–8.
Jacobson MA,de Miranda P, Gordon SM, Blum MR, Volberding P, Mills J. Prolonged pancytopenia due to combined ganciclovir and zidovudine therapy. J Infect Dis (1988) 158, 489–
90.
Pinching AJ,Helbert M, Peddle B, Robinson D, Janes K, Gor D, Jeffries DJ, Stoneham C,Mitchell D, Kocsis AE, Mann J, Forster SM, Harris JRW. Clinical experience with zidovudine for patients with acquired immune deficiency syndrome and acquired immune deficiency syndrome-related complex. J Infect (1989) 18 (Suppl 1), 33–40.
Prichard MN,Prichard LE, Baguley WA, Nassiri MR, Shipman C. Three-dimensional analysis of the synergistic cytotoxicity of ganciclovir and zidovudine. Antimicrob Agents Chemother (1991) 35, 1060–5.
Medina DJ,Hsiung GD, Mellors JW. Ganciclovir antagonizes the anti-human immunodeficiency virus type 1 activity of zidovudine and didanosine in vitro. Antimicrob Agents Chemother (1992) 36, 1127–30.