C3.1 R1: Perform and document the application of pharmacokinetics to clinical practice in a unique patient population (2/2)

I recommended a dose of low molecular weight heparin (dalteparin) in a 36 year old obese female with recurrent provoked pulmonary embolism on treatment with apixaban. The patient weighed approximately 125kg and had a BMI of 41.8. Observational data suggests that using actual weight for dalteparin dosing is safe and there is no data to support efficacy of the manufacturer suggested dose cap commonly reported at 18,000 units sc daily. The question that arose from discussion with the medical team was around the utility of once daily vs. twice daily dosing, given the high dose required (25,000 units sc daily). A 2013 Cochrane review found that once daily injections of LMWH were as effective and safe as twice daily injections of LMWH, but included only a small number of obese patients. Obesity itself can alter the pharmacokinetics of drugs, depending on the drugs specific PK properties. For example, drugs that are lipophilic can have an increased volume of distribution (Vd) in obese patients. Despite potential alterations in clearance in obese patients, clearance rates of most medications remain unchanged (clearance of some hydrophilic medications may be slightly increased). Dalteparin is hydrophilic so we would not expect too much deviation from a normal dose/response relationship vs. a patient with normal weight. However given the high dose of dalteparin required in an obese patient, which typically would require 2 separate pre-filled syringes for outpatient use, twice daily dosing may make more sense. We can also apply the principles of pharmacokinetics to justify a hypothetical benefit from twice daily dosing on safety. With once daily dosing you would expect to see an initial large spike in drug level (well above the therapeutic range) followed by a steady fall in level down into the therapeutic range. The initial large spike in drug level could be the time where bleed risk is highest without an added benefit for efficacy (higher than therapeutic range). Twice daily dosing may eliminate the initial spike in serum drug level after a high once daily dose, with serum drug levels spending more time in the therapeutic range (and less time above) than in once daily dosing. This could hypothetically result in a lower bleeding risk. As such, I recommended that the patient inject one 15,000 unit pre-filled syringe qAM and one 10,000 unit pre-filled syringe qPM.

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