In vivorecovery of factor VIII and factor IX: intra‐ and interindividual variance in a clinical setting

Abstract

In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL1 per U kg1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5-67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13-69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.

Pharmacokinetics and dose requirements of factor VIII over the age range 3–74 years

“…V1, on the other hand, was directly proportional to body weight over the whole age range. This agrees with a previous observation [13] that in vivo recovery (C max divided by dose) of FVIII did not show any relationship to age.…”

“…The third one [2] was a controlled study on the cost-effectiveness of PK-based dosing in 21 patients, which comprised 57 study occasions (1-4 per patient, separated by 2-9 months; 1994-1995) and contributed 221 FVIII:C values. The fourth (1996-1997; described briefly in [13]) was an investigation on the putative influence of low-dose warfarin on the disposition of FVIII:C. The patients were randomised to receive either warfarin 1.25 mg/day orally or placebo in a cross-over fashion. Two weeks after the start of the medication, FVIII was infused over 10 min at a dose of 50 U/kg.…”

“…Relationships of FVIII PK with patient characteristics have been investigated in several studies [2,[6][7][8][9][10][11][12][13][14] on limited numbers of patients. Weight-adjusted clearance (CL) of FVIII (i.e.…”

“…between study occasions, were estimated according to a published procedure [16]. The model was then tested by application to a set of sparse data obtained in clinical practice [13,18], collected from the medical records of 16 patients from 42 visits to the outpatient clinic. Finally, dose requirements to maintain a prophylactic 0.01 U/mL trough level of FVIII were estimated as previously described [1,2] for all patients.…”

Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia

“…IVR is therefore less accurate than half-life, which is determined from a number of data points, or CL which is determined using all data points on a FVIII/FIX level vs. time curve [4,6,10,47,48]. IVR consequently shows very marked inter-occasion variance when measured repeatedly in the same patient [49]. Furthermore, IVR measured as (IU dL ) )1 is affected by the patientÕs weight because blood volume is not proportional to weight.…”