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It is one thing to observe the effects of a drug in a single patient; it is quite another to conduct research into the effects of a drug in an entire population. Yet these studies are crucial in helping researchers see the bigger picture and refine the ideal dosage for any individual patient. 

This is the express aim of pharmacokinetics (PK)-guided dosing. It uses results collected from accurate and validated PK models to allow researchers to prospectively predict data. Physicians are then able to make choices on which PK models best suit the patients under their care and decide the ideal dosing for the prescribed drug. 

Goedhart and colleagues did a fantastic job in conducting a thorough literature review concerning PK modeling for factor concentrates in hemophilia. In their study published in Blood Advances, the team searched for publications with keywords concerning hemophilia PK modeling. Their search yielded 85 publications, of which 26 were finally included. In addition, they added another study by backward citation, leading to a grand total of 27 studies used in the review. 

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“This review provides a detailed overview of data used for published population PK models for factor VIII (FVIII) and factor IX (FIX) concentrates, to support physicians in their choices of which model best suits each patient,” they wrote. 

We will be looking at some of the results of their study, and more importantly, discussing the profound value of PK modeling in guiding modern clinical decision-making. 

From Data to Patient 

The findings of Goedhart et al are sweeping in their scope and highly technical. For this article we will highlight a few key findings based on their PK models for both for FVIII and FIX concentrates: 

  • The research team was able to retrieve 20 models for FVIII concentrates and 7 models for FIX concentrates. 
  • A total of 22 out of 27 patient models included pediatric patients (patients aged less than 18 years); however, only 4 reported detailed demographic information. Based on the maximum weight of patients reported, overweight patients appear to be included in most studies. (The rule of thumb in PK-modeling is to include as many demographic details as possible.)
  • Most models (26 out of 27) detailed the assay used to measure factor levels, but only 16 out of 17 models named the reagents used in their studies. 
  • Six models have been validated using a subset of the data. They were also validated by simulations. 

With these findings, clinicians have a decision to make about how to use this data in their own practice. Goedhart et al wrote, “Clinicians or clinical pharmacologists, who treat patients with PK guided dosing, should evaluate whether the population PK model is suitable for each individual patient, based on the data used to construct the model.” 

Read more about hemophilia patient education 

Goedhart and colleagues provide us with a list of principles to follow when making PK models. If a factor concentrate is approved for all age groups (including children), then corresponding PK models should include and describe pediatric patients too. In addition, patients with weight categories who fall under/above normal limits (ie, underweight and overweight/obese patients) should also be included in PK models. 

Goedhart and colleagues wrote that “when performing PK guidance, it is essential that laboratory specifications, both of the patient populations used to construct the models as well as the patients who receive PK guidance, are reported and taken into account, preferably in accordance with international guidelines.” In other words, PK models work best when they do indeed closely resemble the population that they are studying, and every effort should be made to minimize any loopholes that contradict this principle. 

Lucas and Martin, in their paper on the PK-guided dosing of new oral cancer agents, described their perspective on the importance of this practice. Most new cancer oral agents are marketed at a single dose based on clinical studies. However, it is common knowledge that clinical studies often exclude, for example, overweight individuals (as the testing of new drugs comes with inherent risks). Normally, body surface area is used to determine drug dosing; however, “this strategy adjusts only for height and weight and for many drugs is of limited utility in reducing inter-individual variability in exposure,” they wrote. 

New oral cancer agents often make use of simplified fixed-dosing regimens, which although done with the best of intentions, still fall short in accounting for variations among individual patients.

“Particularly for agents with a narrow therapeutic window, it is important that additional variables contributing to drug disposition (such as age, sex, and genetic polymorphisms) are incorporated in individual dosing regimens,” Lucas and Martin opined. 

Putting Patients First 

Because drug dosing ultimately affects efficacy and toxicity, it is important for physicians to get it right to the best of their ability. Hence, PK-guided dosing goes a long way in presenting physicians with a more accurate picture of how drug dosing varies and affects individual patients in a population.

In this regard, Lucas and Martin concur with the purpose of PK-guided dosing as spelled out by Goedhart and colleagues, writing that “it provides general guidance so that oncologists can themselves consider what an appropriate dose might be for an individual patient for whom the evidence is not available.”


Goedhart T, Bukkems LH, Zwaan CM, Mathôt R, Cnossen MH. Population pharmacokinetic modeling of factor concentrates in hemophilia: an overview and evaluation of best practiceBlood Adv. Published online September 10, 2021. doi:10.1182/bloodadvances.2021005096

Lucas CJ, Martin JH. Pharmacokinetic-guided dosing of new oral cancer agentsJ Clin Pharmacol. Published online September 15, 2017. doi:10.1002/jcph.937