My name is Joshua Kiptoo, a member of the Uganda chapter of Pharmacometrics Africa and a practicing clinical pharmacist in Uganda. Like many other life concepts, I have appreciated that “how” one communicates a scientific concept is as (if not more) important as “what” one intends to communicate. To me, unraveling the ‘how‘ when communicating the concept of “modeling” is critical in understanding the growing popularity of pharmacokinetic modeling in the past decades. Not only is the phrase “Physiologically Based Pharmacokinetic (PBPK) modeling” a mouthful of words to fit in one breath, but also a concept that sounds complex at the first hearing.
Thinking about how people facilitate understanding of perceived ‘complex’ subjects like PBPK modeling, the idea that rang ‘closest to home’ was the use of human mannequins in our clothes shopping stores. In Uganda, tailoring is still a big business and most of us will have our clothes designed and tailor-made for ‘that’ special occasion. To best select tailor-made clothes that best fits an individual’s preference, a vendor may require a mannequin as an additional investment in the business. You can only better appreciate your potential clothes when hung on an appropriate mannequin (‘model’) with the right shape, size, and design (‘dosage regimen’) that is most likely to meet your individual needs. Quite often, we look at the chest and shoulders designs, the waist size, and overall height of the clothing on display. Such is the concept of modeling, and a model that better suits the needs of an individual is much preferable.
As a PhD scholar at the Infectious Diseases Institute (IDI), you get the opportunity to connect and interact with experts and leaders in clinical pharmacology research and practice. The 2024 PBPK workshop held in Kampala brought together distinguished scientists and professionals in the health sector, research, academia, regulation, and industry. The common denominator among all the attendees was the interest in optimising medication use among patient populations with complex care needs, who are often excluded from routine clinical research studies. These include breastfeeding women and their infants, pregnant women, and individuals with impaired organ functions etc.
The 3-day workshop was not complete without one prominent face that stood out – Dr. Karen Rowland Yeo, who is the senior Vice President, Client & Regulatory strategy at Certara (Simcyp Division) with extensive experience in PBPK modeling. What stood out for me was Karen’s positive energy, fun personality, and willingness to help with all aspects of PBPK modeling. I was very impressed with her ability to share complex details in such a relatable manner. I took the opportunity to follow up on some of the amazing speakers through social media and other platforms, and I’m glad I did. The articles and insights that they shared proved very useful in my work as a PBPK scholar at Makerere University. In August 2024, The Pharmacometrics – Uganda chapter (hosted at the Infectious Diseases Institute) kick started a monthly virtual seminar series on the relevance of pharmacometrics in clinical research and drug development. Karen generously carved out time in her schedule to share about a topic she is very passionate about – PBPK modeling in lactation. Her contributions to scientific publications have certainly expanded the role of PBPK modeling in guiding clinical and regulatory decision making on pharmacotherapy. Together with the rest of the Uganda Chapter, we were amazed to see young professionals, trainees, and leading scientists register for the event.
On the day of the event Karen made a fantastic presentation, providing insights from her career as a PBPK modeler and the application of PBPK modeling to help guide regulatory labeling of moxidectin dosing in breastfeeding mothers. Her inspiration to pursue excellence in PBPK modeling world relates directly to her story and experiences in Africa, including South Africa, Liberia, Congo, Zimbabwe etc., with most communities endemic with neglected tropical diseases like Onchocerciasis (responsible for river blindness). From her experience of using medicines in early childhood, Karen says “I grew up in Zimbabwe where I often had to take medicine for several diseases like malaria, but all I remember was that they made me feel awful.. “.
The WHO recommends multiple dosing of Ivermectin for the treatment of Onchocerciasis, with a clear indication of the extend Ivermectin transfer into breast milk, and the recommendation on its use only after the first week of childbirth among mothers with intend to breastfeed their infants. However, the U.S Food and Drug Administration (FDA) approved a newer molecule – Moxidectin (8 mg, single dose) for the treatment of Onchocerciasis, due to its longer terminal elimination half-life and the resultant reduction in microfilaridermia, offering potential logistical and therapeutic advantages than Ivermectin for Mass Drug Administration (MDA) treatment programs. Much is known about the pharmacology and pharmacokinetics of Moxidectin in people aged 12 years and older, but clinically relevant recommendations for breastfeeding mothers are insufficient.
Ojara and colleagues reported that only about 2 in 10 drugs eligible for use in MDA programs, have some scientific evidence to inform their use when a mother is breastfeeding. Breastfeeding women are potential beneficiaries of MDA programs, however, maternal anxiety and missed benefits of maternal drug use and infant breastfeeding may hamper progress of optimal drug use especially in Onchocerciasis endemic regions. . By integrating population (PopPK) and physiologically based pharmacokinetic (PBPK) modeling approaches to establish the likely time-course and level of Moxidectin exposure in infants via breast milk, Karen’s work intended to inform Moxidectin lactation dosing recommendations. It was reported that Moxidectin accumulation in breast milk followed a similar pattern to those of plasma, with maximum concentrations occurring approximately 4 hours after dosing followed by a rapid decline in both plasma and breast milk. It was concluded that in as early as 48 hours following maternal use of Moxidectin, breastfeeding can safely resume as the amount of drug received by the infant via breast milk is below the EMA and FDA safety thresholds. The Moxidectin ‘case study’ demonstrates how useful PBPK modeling is in informing medication use during breastfeeding. In regard to the availability of guidance in drug labels, Karen remarked on the fact that “..whereas data from clinical lactation studies is collected, and the toxicokinetic data may be available from animal studies; oftentimes as is the case with moxidectin, no specific labeling guidance regarding those recommendation are actually made, and therefore it is left to the healthcare professional to make decisions. ”
Sometimes we are not sure if actual decisions can be made without meeting the huge financial cost and other complexities of obtaining clinical data from clinical lactation studies. But in her closing remarks, Dr. Karen pointed out the motivation that should drive the use of PBPK modeling, saying that “..there is always that philosophical question whether PBPK modeling can be used to predict or optimize doses in special populations, and whether we are there yet with respect to data. PBPK models are data driven and I think we should be using them now, and even if we are not after a pinpoint, accurate dose, what they can help us with is to support the clinical data that we have.. “. This can be exemplified by the reality that the work on Moxidectin led to a change in labeling recommendation by the FDA, which will see more mothers breastfeed their babies without anxiety and the uncertainty of their babies being harmed by medicines in breast milk. More details on the Moxidectin case study can be found here.