Case Study 2: Assessing the reproductive safety of reverse transcriptase inhibitors in human uterine tissues

This case study describes the use of human uterine tissue to study safety liabilities of anti-HIV agent daprivine by Biopta. The uterine tissue model replaces tests using mice or rats to measure the effect of the drug on uterine contractility. For more information on this case study please contact the NC3Rs.

Background: During a scientific advice consultation with the EMA, a request was made to investigate pharmacological effects on organs close to the application site.  Consequently, an investigation into the effect of dapivirine on human ex vivo uterine contractility was conducted at Biopta in order to profile any potential adverse effects.

Aims: The aim of the project was to determine whether dapivirine could alter the frequency and amplitude of human spontaneous uterine contractions.

Results:

  • A positive control drug, oxytocin (200 nM) caused an increase in the frequency of spontaneous contractions of isolated strips of human uterus – Figure 1.
  • In contrast, dapivirine had no effect on uterine contractility at 500 nM and 5mM (Figure 2).
  • There was no effect of dapivirine on the peak area under the curve (figure 2), while the positive control forskolin markedly inhibited contractility.
  • Based on the use of human fresh tissue as a method to predict potential adverse effects, these data suggest that a direct effect of dapivirine on uterine contractility is unlikely.
Figure 1 – the effect of oxytocin (200 nM) on spontaneous contractions of human isolated uterine tissues set up in organ baths for measurement of contractile force. 

Impact: By using human fresh uterine tissues, an important but potentially difficult question was able to be addressed, which has helped to de-risk the clinical development of dapivirine. This may have also reduced the need for ex vivo or in vivo studies in animal uterine tissues.