Pharmacokinetics of recombinant factor VIII (Kogenate‐FS^®) in children and causes of inter‐patient pharmacokinetic variability

Abstract

Understanding the pharmacokinetics (PK) of factor VIII (FVIII) is important in the management of patients with haemophilia A. We studied the PK of FVIII in order to determine aetiological factors contributing to PK variability of FVIII in children. Twenty children with haemophilia A (mean age 12.8 years) were administered a single bolus of 50 U kg )1 of recombinant FVIII (rFVIII; Kogenate-FS Ò , Bayer).The mean incremental FVIII recovery was 1.87 (U mL )1 )/(U kg )1 ) (range: 1.25-2.76) and the mean FVIII half-life was 10.7 h (range: 7.8-15.3). FVIII recovery was positively correlated with body surface area (BSA; P ¼ 0.04). FVIII half-life was positively correlated with preinfusion levels of von Willebrand factor antigen (VWF:Ag) (P ¼ 0.0001) and was reduced in patients (n ¼ 6) with very low FVIII inhibitor titres (<0.5 BU) vs. those (n ¼ 14) with negative inhibitor titres (P ¼ 0.06). These observations suggest that (i) young children with haemophilia in comparison with adults have a low recovery of FVIII and that this might be explained by differences in body composition (BSA, plasma volume), (ii) levels of VWF:Ag may explain some of the differences in the half-life and clearance of FVIII and (iii) very low inhibitor titres, previously regarded as clinically insignificant, may actually be significant and should be evaluated in the context of PK studies.

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

“…It was previously found [9] that the elimination t1/2 of FVIII was shorter in haemophilia patients with blood group O than in those with blood group A. The effect of blood group appears to be modest, however, and it was not significant in our or in an earlier [11,12] investigation.…”

“…Relationships of CL and t1/2 with plasma level of von Willebrand factor have been reported [8][9][10][11] but also refuted [12]. An increased CL and shorter t1/2 of FVIII in patients with blood group O [9] could not be confirmed in other studies [11,12]. These investigations were mostly performed by two-step methodology, i.e.…”

“…in millilitres per hour per kilogram) has generally been found to decrease with age and/or body weight (BW) during growth from infancy to adulthood, with a corresponding increase in terminal half-life (t1/2) [2,7,10,14]. Relationships of CL and t1/2 with plasma level of von Willebrand factor have been reported [8][9][10][11] but also refuted [12]. An increased CL and shorter t1/2 of FVIII in patients with blood group O [9] could not be confirmed in other studies [11,12].…”

“…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.…”

Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight

“…Therefore, several studies have aimed to clarify relationships between such characteristics and measured PK parameter values. [3][4][5][6][7][8][9][10][11][12][13] We have previously published a PK study on recombinant FVIII, comparing the results from patients 1 to 6 years of age and 10 to 65 years of age. 13 In brief, in vivo recovery was lower, BW-adjusted clearance (CL) was higher and elimination half-life (t 1 ⁄2) was on average shorter in children than in adults.…”