Phenprocoumon Concentration Research Articles

Quantifying the Effect of Covariates on Concentrations and Effects of Steady-State Phenprocoumon Using a Population Pharmacokinetic/Pharmacodynamic Model

The oral anticoagulant phenprocoumon, similar to other vitamin K antagonists, is characterized by pronounced interindividual variability in the doses needed to achieve the desired therapeutic effect. Previous studies assessed the effect of genetic and demographic covariates on empirical dose requirements of phenprocoumon to enable individualized dose prediction. The aim of the present study was to quantify major sources of interindividual variability separately on the pharmacokinetics and pharmacodynamics of phenprocoumon using a population pharmacokinetic-pharmacodynamic model. A single steady-state blood sample was collected from 278 patients and assayed by liquid chromatography-tandem mass spectrometry for phenprocoumon and its metabolites. Genotyping was performed for variants of the cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex, subunit 1 (VKORC1) genes. Effects were quantified by international normalized ratio (INR). Data were analyzed simultaneously using NONMEM VII. The model confirmed CYP2C9 and VKORC1 variants as the major predictors of variability in phenprocoumon concentrations and effects, together with body weight, age, comedication with CYP3A modifiers (i.e. inhibitors or inducers) and presence of atrial fibrillation. These covariates explained 50.0 % of the observed variability in the model parameters. Phenprocoumon clearance fractions mediated per CYP2C9 allele were 13.4, 9.5 and 5.7 mL/h for the 1, 2 and 3 variants, respectively. An additional clearance fraction of 5.3 mL/h was independent of CYP2C9 activity. Homozygous VKORC1 wild-type carriers were estimated to have a 2.13-fold higher phenprocoumon exposure requirement than homozygous 1173 C>T carriers to achieve the same effect on INR. The model provides a deeper insight in the separate pharmacokinetic and pharmacodynamic parts of phenprocoumon action. Thus, it provides important information for individualized dose prediction, with the option to include further covariates not studied here with known effects on individual pharmacokinetic or pharmacodynamic processes.

Pregnancy outcome after maternal intoxication with phenprocoumon

Vitamin K antagonists (VKA) like phenprocoumon may be prescribed for certain indications despite pregnancy [1]. These drugs are able to cross the placenta, to reach the foetal blood circulation and to harm the foetus [2]. Case reports of VKA embryopathy describe mental retardation, optic atrophy, cleft lip and palate, nasal hypoplasia and stippling of bone. In addition there is the risk of spontaneous abortion, stillbirth and bleeding complications in the neonate [3, 4]. If there is nevertheless an indication requiring ingestion of VKAs during pregnancy, switching to another anticoagulant treatment is definitely necessary not later than in the 36th week to avoid neonatal intracranial haemorrhage under spontaneous delivery [5, 6]. However, occasionally the obstetrician may be faced with pregnant women who turn out to be severely poisoned by VKAs shortly before the appointed day of delivery. Recently, we were involved in the care of such a rare case of a pregnant woman with massive VKA intoxication. A 26-year-old pregnant woman came to our hospital in the 38th week of pregnancy because of back pain. A routine screening test detected the international normalized ratio (INR), a derived measure of the prothrombin time, as being unmeasurable (i.e. >10) and the activated partial thromboplastin time (aPTT) exceeded 180 s (normal range 26–34 s). The patient denied any anticoagulant treatment. Detailed analysis of clotting factors showed the following results: factor II 3% (normal range 65–130%), factor VII 3% (normal range 70–140%), factor IX 6% (normal range 60–160%), and factor X 2% (normal range 65–125%). A potent inhibitor of these factors was ruled out. A toxicological examination by liquid chromatography-mass spectrometry detected a phenprocoumon concentration of 5913 ng ml−1. For comparison, the therapeutic concentration ranges between 1000 and 3500 ng ml−1[7]. Immediately, 2000 IE prothrombin complex concentrate and 500 IE antithrombin were administered. From day 1 to day 3, the patient received up to 30 mg vitamin K orally per day, thereafter 10 mg until day 16 after admission when she delivered a female baby by Caesarean section without bleeding complications. The coagulation parameters of the mother had already normalized 7 days earlier. Coagulation tests from cord blood showed an INR of 1.23, an aPTT of 58.2 s (normal range for newborn [8] 37.1–48.7 s), a factor II of 44%, a factor VII of 41%, a factor IX of 29% and a factor X of 50%. The phenprocoumon concentration was 297 ng ml−1. The child showed no sign of foetal VKA syndrome, received vitamin K, and was able to leave the hospital after 5 days in good general condition. The almost complete lack of data on the haemostatic capacity in unborn children of mothers suffering from VKA poisoning is a difficult clinical challenge. Of course, it is ethically completely unacceptable to generate such data by periodic cordocentesis. Therefore, it is vital to report cases, pre-partum laboratory findings in mothers and post-partum laboratory findings in newborn children in this regard to clarify the optimal treatment of the mother and the optimal day and route of delivery, if VKA intoxication has been detected shortly before the appointed day of delivery. Our measurements suggest that a spontaneous delivery should not be risked earlier than 1 to 2 weeks after normalization of the mother's coagulation parameters.

Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters

PurposeThe anticoagulation response to vitamin K antagonists is characterised by high inter-individual variability. The impact of single nucleotide polymorphisms (SNPs) in several genes of enzymes involved in the vitamin K cycle on phenprocoumon dose variability and phenprocoumon plasma concentrations is still under investigation.MethodsWe assessed the influence of VKORC1 c.-1639G>A, CYP2C9*2, CYP2C9*3, CYP4F2 c.1297G>A, CALU c.*4A>G, EPHX1 c.337T>C, GGCX c.214+597G>A, F7 c.-402G>A, F7 c.-401G>T, PROC c.-228C>T and PROC c.-215G>A along with clinical and demographic parameters on steady-state phenprocoumon therapy in 75 patients. A prediction model was developed for total phenprocoumon plasma concentrations and daily phenprocoumon doses required for therapeutic anticoagulation.ResultsThe VKORC1 c.-1639 genotype was the main predictor of the phenprocoumon daily dose (adjusted R2 = 37.6%) and the total phenprocoumon concentration (adjusted R2 = 38.3%). CYP2C9 affected the phenprocoumon concentration, but not the dose requirements. SNPs in the other genes of the vitamin K cycle, concomitant medication, nicotine use and alcohol consumption did not predict phenprocoumon concentrations and phenprocoumon dose requirements in a multiple linear regression model. Phenprocoumon concentrations were predicted by VKORC1 c.-1639, CYP2C9 genotype, age and BMI. The final prediction model for the daily phenprocoumon dose requirements comprised VKORC1 c.-1639 genotype, age and height accounting for 48.6% of the inter-individual variability.ConclusionsA rough prediction of phenprocoumon maintenance doses can be achieved by a limited set of parameters (VKORC1, age, height). The investigated SNPs in CYP4F2, CALU, EPHX1, GGCX, F7, and PROC did not improve the predictive value of a pharmacogenetic-based dosing equation for phenprocoumon.

Phenprocoumon poisonings

Phenprocoumon is a derivative of coumarin, used as a preventative anticoagulant and in the treatment of thromboembolisms. On account of its pharmacodynamic and pharmacokinetic properties, strict surveillance of the patient is necessary. We report on two cases of undocumented administration of this active pharmaceutical ingredient. A 57-year-old woman was discovered by her husband in an inanimate state. The post-mortem examination revealed many extensive haematomas. On account of a suspicion of third-party negligence, an autopsy was performed the same day, during which was established that the cause of death was a clotting abnormality, the cause of which remained unclear. Toxicological analyses revealed a concentration of phenprocoumon of 7.8 mg/l. A 76-year-old man admitted himself to hospital immediately upon returning from a stay abroad. In hospital, extensive haematomas and a massive clotting abnormality (prothrombin ratio < 10%) were discovered. A blood sample taken the following day yielded evidence of a phenprocoumon concentration of 3.1 mg/l. According to his general practitioner, no corresponding medications had been prescribed. Suspicion of foul play in the introduction of this active agent resulted in a police investigation. Both cases demonstrate the necessity of toxicological analyses in cases of clotting abnormalities.

Determination of phenprocoumon in plasma and urine using at-line solid-phase extraction-capillary electrophoresis

The use of capillary electrophoresis (CE) for the analysis of biological samples is rather problematic because of the large number of interferences present in the matrix. One of the possibilities to solve such problems is to couple solid-phase extraction (SPE) at-line with CE, a technique developed in our laboratory. In this study at-line SPE–CE is performed for the determination of the anticoagulant phenprocoumon in biological fluids. Plasma samples are injected after the addition of 1 vol.% of formic acid to release the drug from binding proteins, while urine samples can be directly injected. The procedure is linear between 0.2 and 30 μg ml −1 with a correlation coefficient, r 2, of 0.9996. The detection limit in plasma is 0.1 μg ml −1, which is fully adequate in view of the concentrations, that have to be dealt with in practice. The phenprocoumon concentration in a plasma sample of a patient treated with the anticoagulant was 3.8 μg ml −1.

055 Monitoring phenprocoumon concentrations in serum and serum water by HPLC

055 Monitoring phenprocoumon concentrations in serum and serum water by HPLC

Pharmacokinetic and pharmacodynamic interactions between phenprocoumon and atenolol or metoprolol.

Pharmacological interactions in both directions between phenprocoumon and atenolol and metoprolol were investigated using a crossover trial. Co-administration of phenprocoumon did not significantly affect Cmax, tmax, t1/2,22, AUC for atenolol or metoprolol. Co-administration of metoprolol, but not atenolol, increased mean plasma phenprocoumon concentrations 4 and 6 h after dosing and was caused by a decrease in the apparent volume of distribution. This increase in plasma phenprocoumon was not associated with an increase in prothrombin time or in the total area under the concentration-time curve. Although the transient increase of phenprocoumon plasma levels caused by metoprolol may be of little clinical significance after a single dose of phenprocoumon, a more important alteration in phenprocoumon disposition and effect should be considered in individual patients on long-term therapy.

Phenylbutazone and Sulfinpyrazone Interaction With Oral Anticoagulant Phenprocoumon

To compare the marked hypoprothrombinemic augmentation in man of racemic warfarin sodium by the pyrazolons phenylbutazone and sulfinpyrazone with that of the coumarin anticoagulant phenprocoumon, these interactions were studied prospectively in six normal subjects. Large single doses of racemic phenprocoumon, 0.6 mg/kg orally, were administered with and without daily phenylbutazone, 300 mg, or sulfinpyrazone, 400 mg, beginning three days before phenprocoumon and continuing for 14 days. Daily blood samples were drawn for phenprocoumon content and one-stage prothrombin time. Phenylbutazone markedly increased both the phenprocoumon concentrations and prothrombin times, whereas sulfinpyrazone did not.

Medication compliance in long term phenprocoumon therapy

Medication compliance was assessed by a cross-sectional study of 225 patients, chosen at random from the records of a thrombosis service. The serum phenprocoumon concentration, in relation to the prescribed dose, was found to be unacceptably low in eleven patients. It is concluded that non-compliance occurs only infrequently. Thrombotest values were of little help in detecting non-compliance.

Interaction study between phenprocoumon and flurbiprofen.

The effects of flurbiprofen on various coagulation and haemostasis parameters were studied in 19 patients adequately anticoagulated on a fixed dose of phenprocoumon. Laboratory controls were performed 5 times at weekly intervals. Flurbiprofen 50 mg 3-times daily was given for 2 weeks after an initial control period of 2 weeks. The last control followed 1 week after cessation of flurbiprofen. All changes observed during the administration of flurbiprofen were quantitatively moderate; some reached statistical significance. The prothrombin time (%) Factor II and Factor X values fell; Factor II values remained unchanged. Factor IX values fell only in the first week on flurbiprofen and reached control values thereafter. Phenprocoumon concentration remained constant throughout. There was no change in spontaneous platelet aggregation. Although there was a slight, statistically significant increase in the Ivy bleeding time, it remained within the normal range. These findings suggest that the interference of flurbiprofen with oral anticoagulation is minimal and probably of no clinical relevance.