Prenatal developmental toxicity evaluation of 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T) co-administered to Swiss Albino (CD-1) mice.
BACKGROUND
In pregnant women, antiretroviral drugs improve maternal health and reduce vertical transmission of human immunodeficiency virus to the infant. However, few nonclinical studies have examined the potential for adverse drug interactions.


METHODS
On gestational days (GD) 6-16, mice were dosed with vehicle, ddI (360, 1440, or 2,880 mg/kg/day, p.o.), d4T (60, 240, or 480), or ddI/d4T combinations (360/60, 1,440/240, or 2,880/480). Daily doses were divided into two equal parts that were administered >or=6-hr apart. Body weight, clinical signs, and feed consumption were monitored. Pregnancies (22-24/group) were confirmed at necropsy. Maternal liver and gravid uterine weights (GUW), uterine implants (resorption, live or dead fetus), fetal body weight, gender, and morphologic anomalies (external, visceral, skeletal) were recorded.


RESULTS
Maternal body weight, clinical signs, and GUW were unaffected. Maternal weight change corrected for GUW was greater than controls at 60 and 480 d4T. Relative feed consumption during treatment was increased relative to controls at 1,440 and 2,880 ddI and 2,880/480 ddI/d4T. Relative maternal liver weight was elevated above controls at 240 and 480 d4T and 2,880/480 ddI/d4T, and above the constituent dose of ddI at 1,440/240 and 2,880/480 ddI/d4T. Liver weight was not affected by ddI and there was no significant drug interaction. Prenatal mortality and morphologic anomalies were not increased. Fetal body weight showed only a decreasing trend for ddI/d4T, no effect for ddI or d4T, and no statistically significant drug interaction.


CONCLUSIONS
In pregnant mice, ddI/d4T combinations were not associated with well-defined developmental toxicity or adverse drug interactions.
Price
Catherine J
CJ
Life Sciences and Toxicology, RTI International, Research Triangle Park, North Carolina 27709-2194, USA. cjp@rti.org
George
Julia D
JD
Marr
Melissa C
MC
Myers
Christina B
CB
Bieler
Gayle S
GS
Williams
Rick L
RL
Jahnke
Gloria D
GD
D000818:Animals; D021461:Animals, Outbred Strains; D016049:Didanosine / Q000008:administration & dosage* / Q000633:toxicity*; D010064:Embryo Implantation / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005313:Fetal Death; D020567:Fetal Weight / Q000187:drug effects; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects* / Q000196:embryology*; D008098:Litter Size / Q000187:drug effects; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D018119:Stavudine / Q000008:administration & dosage* / Q000633:toxicity*
D018119:Stavudine; D016049:Didanosine