Evaluation of the phosphodiesterase 3 inhibitor ORG 9935 as a contraceptive in female macaques: initial trials

Abstract

Background: The study was conducted to determine whether a phosphodiesterase (PDE) 3 inhibitor has potential as a novel contraceptive in primates.

Methods: Regularly cycling adult female cynomolgus macaques of proven fertility (n=16) were treated for 7 months with placebo (controls) or the PDE3 inhibitor ORG 9935 as a daily food treat (150 mg/kg) or as a weekly depot injection (150 mg/kg, sc). After 1 month, a male of proven fertility was introduced into each group. Females underwent weekly monitoring of progesterone (P) and ultrasound evaluation for pregnancy if P remained elevated (1.0 ng/mL) >3 weeks. ORG 9935 values were evaluated using high-performance liquid chromatography.

Results: Overall, the pregnancy rate in ORG 9935-treated monkeys (4/8, 50%) did not differ from controls (7/8, 88%; p=.5). However, no animal became pregnant in a cycle when the serum level of ORG 9935 exceeded 300 nmol/L. Moreover, two treated monkeys who mated throughout the treatment phase and did not conceive became pregnant within four cycles after stopping ORG 9935. The other two animals were discontinued prematurely from the protocol.

Conclusions: These results demonstrate that ORG 9935 may prevent pregnancy in primates at serum concentrations above 300 nmol/L and that the effect is reversible.

Fig. 1

Design of the contraceptive study.

Fig. 2

Pregnancies during the treatment and recovery cycle. One control animal was never mated during 6 ovulatory cycles. She became pregnant when she was co-housed with another male during the reversibility phase during the first cycle that mating was confirmed.

Fig. 3

Scatterplot of ORG 9935 levels (nmol/L) during cycles where pregnancy did (white circles) and did not (black squares) occur. The dotted line shows the threshold (300 nmol/L above which pregnancy did not occur. There were 4 pregnancies in the treated animals. Two of the low values were samples obtained from one female during a pregnant cycle.

Fig. 4

Heart rate response of a female rhesus macaque to oral treatment with Org 9935 200 mg/kg once/day (200 qd), 200 mg/kg twice/day (200 BID), and 400 mg/kg once/day (400 qd). Arrows indicate drug dosing. Note normal variations in daily heart rate in untreated animals, and that heart rate returns to pre-treatment levels following discontinuation of treatment.

Fig. 5

Heart rate (A) and blood pressure (B) changes observed in a 5 kg rhesus macaque during long-term oral treatment with ORG 9935 at daily doses from 200 mg to 1000 mg/day. The dose (x axis) was increased every 7 days; 200 = 40 mg/kg.