A document by Tirhani Maluleke. Click on the document to view its contents.

Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake ‘traditional’ pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically-based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant comedications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically-based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed. LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolised by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with comedications as they do not induce or inhibit the major drug metabolising enzymes. However, they are victims of DDIs relating to the induction of their metabolising enzymes by concomitantly administered medication. Noteworthy contraindicated comedications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically-significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimise risk.

Pharmacometrics, the mathematical approaches to describe the transfer of drug through different biological compartments, are essential tools in clinical pharmacology research. The ethical necessity to study drugs accurately in the populations where they are to be used is increasingly recognized. To maximise the value of clinical data, study design and analysis must be appropriate. Historically, many datasets have been sent from African countries to better-resourced settings for analysis, but in recent years it has been demonstrated that capacity can be built and sustained within low and middle-income countries (LMIC)3. We report the establishment of the Uganda Chapter of Pharmacometrics Africa, to share learning with other countries seeking to build similar capabilities.

Pharmacometrics Africa is a not-for-profit company registered in South Africa as an established platform for interested groups to establish and run open-access quantitative clinical pharmacology educational programs in partnership with local research organizations and academic groups. Pharmacometric research and clinical application is pivotal in characterising and optimising treatments, especially for complex or understudied populations. The application of pharmacometrics in drug development during recent years has led to an increase in the adoption of this technique in many drug companies and increased the demand for skilled pharmacometricians globally. Stringent regulatory authorities such as the US-FDA and EMA have increasingly populated their review groups with these scientists, further increasing the demand for the expertise and, more importantly, evidencing the impact and importance of pharmacometrics within the drug development cycle. Creative solutions are required to provide adequate training resources for the future. Pharmacometrics is nascent in Africa. Here, we report on establishing the Ugandan Chapter of Pharmacometrics Africa. This aims to transfer primary training responsibility to local institutions and faculty for sustainability and to build upon regional strengths in pharmacometrics. Creating a local centre of excellence will help attract both regional and international collaborations on quantitative clinical pharmacology. We summarize our experience, key lessons learnt and future perspectives.

Aim We aimed to explore the effect of pregnancy on bedaquiline pharmacokinetics and describe bedaquiline exposure in the human milk of mothers treated for rifampicin-resistant TB, where there is no human data available. Methods We performed a longitudinal pharmacokinetic study in pregnant women treated for rifampicin-resistant TB to explore the effect of pregnancy on bedaquiline exposure. Pharmacokinetic sampling was performed at four time-points over six hours in the third trimester, and again at approximately six weeks postpartum. We obtained serial human milk samples from breastfeeding mothers, and a single plasma sample taken from breastfed and non-breastfed infants to assess bedaquiline exposure. We used liquid chromatography-tandem mass spectrometry to perform the human milk and plasma bedaquiline assays, and population pharmacokinetic modelling to interpret the bedaquiline concentrations. Results We recruited 13 women, six of whom completed the ante- and post-partum PK sampling. All participants were HIV-positive on antiretroviral therapy. We observed lower ante- and post-partum bedaquiline exposures than reported in non-pregnant controls. Bedaquiline concentrations in human milk were higher than maternal plasma (milk to maternal plasma ratio: 24:1). A single random plasma bedaquiline and M2 concentration was available in four infants (median age: 6.5 weeks): concentrations in the one breastfed infant were similar to maternal plasma concentrations; concentrations in the three non-breastfed infants were detectable but lower than maternal plasma concentrations. Conclusion We report low exposure of bedaquiline in pregnant women treated for rifampicin-resistant TB. Bedaquiline significantly accumulates in human milk; breastfed infants receive mg/kg doses of bedaquiline equivalent to maternal doses.

It is unfortunately true that clinicians lack the necessary evidence to know how to use medications properly in large sections of the population, and we do not have optimal drugs to use in many Neglected Tropical Diseases (NTDs). NTD’s often disproportionately affect neglected populations such as children and pregnant women. As reliable access to safe, effective preventives and treatments can break the cycle of poverty, illness, and ensuing debility that further perpetuates poverty, it is of paramount importance to investigate and develop new medicines for neglected populations suffering from NTDs. Furthermore, there is not only a need to develop and evaluate novel therapies, but also to ensure that these are affordable, available, and adapted to the communities who need them. With this editorial, the British Pharmacological Society hereby launches a call for high-quality articles focusing on NTDs in special populations, to facilitate the reversal of this dual neglect.

Warfarin has existed for more than seven decades and has been the anticoagulant of choice for many thromboembolic disorders. The recent introduction of direct acting oral anticoagulants (DOACs) has however caused a shift in preference by healthcare professionals all over the world. DOACs have been found to be at least as effective as warfarin in prevention of stroke in patients with atrial fibrillation and in treatment of venous thromboembolism. In sub-Saharan Africa, however, the widespread use of DOACs has been hampered mainly by their higher acquisition costs. As the drugs come off patent, their use in sub-Saharan Africa is likely to increase. However, very few trials have been conducted in African settings, and safety concerns will need to be addressed with further study before widespread adoption into clinical practice.

Patients in sub-Saharan Africa generally have poor anticoagulation control. We review the potential reasons for this poor control, as well as the potential solutions. Challenges include the affordability and centralisation of anticoagulation care, problems with access to medicines and INR monitoring, the lack of locally-validated standardized dosing protocols, and low levels of anticoagulation knowledge among health care workers and patients. Increasing numbers of patients will need anticoagulation in the future because of the epidemiological transition in the region. We propose that locally-developed “warfarin care bundles” which address multiple anticoagulation challenges in combination may be the most appropriate solution in this setting currently.