Aim Long-acting cabotegravir and rilpivirine have been approved to manage HIV in adults, but data regarding safe use in pregnancy are limited. Physiologically-based pharmacokinetic modelling (PBPK) can predict drug disposition in complex populations. Approved dosing regimens were simulated in pregnancy to explore if Ctrough was maintained above target concentrations (664 ng/ml and 50 ng/ml respectively). Methods An adult PBPK model was developed and validated using clinical data of cabotegravir and rilpivirine in non-pregnant adults. This was modified by incorporating pregnancy-induced metabolic and physiological changes. The pregnancy PBPK model was validated with data on oral rilpivirine and raltegravir (UGT1A1 probe substrate) in pregnancy. Acceptance criteria for both adult and pregnancy models was absolute average-fold error (AAFE) < 2 between clinical and simulated values. The pregnancy PBPK model was used to simulate 12 weeks’ disposition of monthly and bimonthly dosing of long-acting cabotegravir and rilpivirine, initiated at different trimesters. Results Models were successfully qualified with all AAFE values below 2. Predicted Ctrough at week 12 for both monthly and bimonthly long-acting cabotegravir was above 664 ng/ml throughout pregnancy. Similarly, predicted Ctrough at week 12 for monthly long-acting rilpivirine was above 50 ng/ml throughout pregnancy. However, for bimonthly rilpivirine administration, predicted Ctrough at week 12 were <50 ng/ml in 1, 0.5, and 2.3% of the pregnant population when initiated in first, second, and third trimester respectively. Conclusion Model predictions suggest monthly and bimonthly long-acting cabotegravir is likely to maintain antiviral efficacy throughout pregnancy. However, bimonthly long-acting rilpivirine requires careful clinical evaluation in pregnancy.

Low- and middle-income countries (LMIC) face unique challenges with regard to the establishment of robust pharmacovigilance systems capable of generating data to inform healthcare policy and practice. These include the limited integration and reliance of pharmacovigilance systems across LMIC despite recent efforts to harmonize pharmacovigilance rules and regulations in several regional economic communities; the need to translate reporting tools into numerous local languages; low numbers of healthcare providers relative to number of patients, with very short consultation times; scarcity of well-trained pharmacovigilance personnel with little or no budgetary support for these activities from national governments; high turnover of pharmacovigilance staff whose training involves a substantial amount of resources; little awareness of pharmacovigilance among healthcare workers, decision makers and consumers; very low spontaneous reporting rates with poor quality reports which hinders robust signal detection analyses; little collaboration between public health programmes and national medicines regulatory authorities; limited investment in pharmacovigilance activities especially during mass drug administration for neglected tropical diseases; high uptake of herbal and traditional medication, mostly by self-medication; disruptive political conflicts jeopardizing fragile systems; and little or no access to drug utilization data which makes it difficult to reliably estimate the true safety risks of medicine use. This review summarises the specific challenges and areas of progress in pharmacovigilance in LMIC with special focus on the situation in Africa.

Pregnant, or potentially pregnant women have historically been excluded from clinical trials of new medications. However, it is increasingly recognised that it is imperative to generate evidence from the population in whom the drugs are likely to be used in order to inform safe, evidence-based shared clinical decision making. Reluctance by researchers and regulators to perform such studies often relates to concerns about risk, particularly to the fetus. However, this must be offset against the risk of untreated disease or using a drug in pregnancy where safety, efficacy and dosing information are not known. This review summarises the historical perspective, the ethical and legal frameworks which inform the conduct of such research, then highlights examples of innovative practice which have enabled high quality, ethical research to proceed to inform the evidence-based use of medication in pregnancy.