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Aims: Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE., Methods and Results: In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters., Conclusion: To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.

Background: Vincristine is one of the cornerstones of the treatment of children with acute lymphoblastic leukaemia (ALL). Constipation, and peripheral and central neurotoxicities are the most common side effects. A comparative study exploring vincristine toxicity in individual patients receiving vincristine with and without azoles, however, is lacking., Methods: In total, 20 paediatric patients with de novo ALL were included. In each patient, vincristine toxicity in the period with and without azole co-medication was retrospectively graded according to the US National Cancer Institute toxicity scale. Statistical analysis was performed using the Wilcoxon signed rank test and McNemar's test., Results: Patients receiving vincristine in combination with azole treatment experienced significantly more constipation and peripheral neurotoxicity (P = 0.001 and P < 0.001, respectively). Vincristine-induced CNS toxicity was only seen in patients (30%) receiving vincristine in combination with azole treatment., Conclusions: Vincristine toxicity is significantly enhanced when combined with azole treatment and can even be life threatening. Therefore, we advise avoidance of the combination of azole and vincristine treatments in patients with ALL.