Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS Clinical Trials Group Study.
OBJECTIVE
To assess the toxicity, efficacy, and pharmacology of combined zidovudine and ganciclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) and serious cytomegalovirus (CMV) disease.


METHODS
Prospective, phase I multicenter trial (ACTG 004) with patients grouped by previous study drug history.


METHODS
Three university-based AIDS Clinical Trials Units sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).


METHODS
Forty-one patients with AIDS-related CMV disease. Previous therapy with either zidovudine or ganciclovir was allowed.


METHODS
Patients were treated with zidovudine, 600 to 1200 mg/d; or, if on ganciclovir maintenance, ganciclovir, 5 mg/kg body weight; blood was sampled for pharmacokinetic studies. The other drug was then administered to the patient with blood sampling and, finally, the two drugs in combination were given. Patients were continued on both drug therapies with dose reduction of zidovudine only for grade 3 or 4 toxicity.


RESULTS
Forty patients were eligible. Hematologic toxicity was frequent, with 9 of the 10 patients requiring dose reductions for grade 3 or 4 toxicity at zidovudine doses of 1200 mg/d. With zidovudine doses of 600 mg/d, 82% experienced such hematologic toxicity. Median survival was 6 months; 10 patients developed intercurrent infection and 19, progressive CMV disease. Pharmacokinetic variables (alpha and beta half-lives, volume of distribution, clearance) were not affected in combination therapy.


CONCLUSIONS
The combination of zidovudine and ganciclovir is poorly tolerated in patients with AIDS and serious-CMV disease, with 82% developing severe to life-threatening hematologic toxicity. Such toxicity is not a result of pharmacologic interactions, drug metabolism, or excretion.
Hochster
H
H
New York University Medical Center, New York.
Dieterich
D
D
Bozzette
S
S
Reichman
R C
RC
Connor
J D
JD
Liebes
L
L
Sonke
R L
RL
Spector
S A
SA
Valentine
F
F
Pettinelli
C
C
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D000284:Administration, Oral; D000328:Adult; D000740:Anemia / Q000139:chemically induced; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003586:Cytomegalovirus Infections / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009503:Neutropenia / Q000139:chemically induced; D011446:Prospective Studies; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
D015215:Zidovudine; D015774:Ganciclovir