Multi-variate analysis of factors governing the pharmacokinetics of exogenous factor VIII in haemophiliacs

Messori, Andrea; Longo, Giovanni; Morfini, Massimo; Cinotti, S.; Filimberti, E.; Giustarini, G.; Ferrini, Pierluigi Rossi

doi:10.1007/bf00637604

Cited by 42 publications

(45 citation statements)

References 18 publications

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“…The pharmacokinetic parameters (table 4) compare well with the results of the in vivo evaluations of factor VIII concentrates in larger patient populations [13], During the evaluation no side effects were observed. The development and production is described of a small pool factor VIII concentrate that is manufactured in Dutch blood banks.…”

Section: In Vivo Evaluationsupporting

confidence: 59%

Development and Small-Scale Production of a Severely Heated Factor VIII Concentrate

Knevelman¹,

Wit²,

Potstra³

et al. 1994

Vox Sanguinis

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The small-scale production of a severely heated factor VIII concentrate is described. As starting material for the production 48 units of fresh frozen plasma from whole-blood donations or 24 units of plasma from apheresis are used. During a glycine and sodium chloride fractionation, contaminating proteins are removed from a pooled extract of single-donor cryoprecipitates. The resulting factor VIII-rich precipitate is redissolved in freeze-drying buffer and this solution is desalted by diafiltration. After filtration, this solution is dispensed into 10 vials and frozen. The product is freeze dried, and heat treated at 80°C for 72 h. The mean yield of the heat-treated product improved from 160 IU factor VIII per liter plasma at the start of the production to 215 IU per liter plasma after a modification of the purification process. The validation of the virus inactivation during freeze-drying and 80°C heat treatment for 72 h showed a reduction of ≥ 7.6 log PFU/ml for Sindbis and a reduction of ≥ 6.4 log TCID(50)/ml for HIV-1. The factor VIII concentrate was clinically tested in 6 patients. It possessed a normal half-life, showed a high recovery and no side effects. A Dutch license was granted in June 1991 and since then this product has been routinely manufactured in three Dutch blood banks.

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Section: In Vivo Evaluationsupporting

confidence: 59%

Development and Small-Scale Production of a Severely Heated Factor VIII Concentrate

Knevelman¹,

Wit²,

Potstra³

et al. 1994

Vox Sanguinis

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“…After the fit of each pharmacokinetic curve by the least-squares method, the population pharmacokinetic parameters of amikacin in our series of neonates were estimated using the standard two-stage (STS) method [8][9][10] To gain more information on the intraindividual variability of amikacin pharmacokinetics, a further analysis was carried out in the subgroup of 20 neonates (18 preterm and 2 at term) in whom a total of at least 4 measurements of amikacin concentration per patient were available and in whom the peak-through sam pling was performed on two separate occasions per patient. In this subgroup, the mean interval between the measurement of the first and the third concentra tion was 84.0 ± 33.8 h (range: 24-156 h).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Amikacin in Neonates

C²,

Fanos³

et al. 1993

Dev Pharmacol Ther

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Only a few data have thus far been published on the pharmacokinetics of amikacin in neonates. To gain further information on this issue, we studied a series of 32 neonates who were treated with amikacin for suspected or documented bacterial infection. Nineteen neonates were preterm (mean gestational age = 32.0 ± 3.6 weeks, mean body weight = 1.74 ± 0.81 kg) while the remaining 13 were full-term (mean body weight = 3.19 ± 0.82 kg). The 32 neonates were given amikacin by intramuscular route. A total of 121 concentrations were measured (average number of concentrations per patient = 3.8; range 3-6). To estimate amikacin pharmacokinetic parameters, the serum concentration values of the drug were fitted to the one-compartment pharmacokinetic model. The calculated pharmacokinetic parameters were the following (mean ± SD): clearance = 64.6 ± 30.8 ml/h/kg; volume of distribution = 0.655 ± 0.414 liters/kg; half-life = 7.6 ± 4.4 h. These results are similar to the values reported previously, with the important exception of the volume of distribution, which was considerably higher in our study. The intraindividual variability of amikacin pharmacokinetics was evaluated by the standard two-stage method yielding an intraindividual variability coefficient of 28.9%. No previous estimate of this parameter has as yet been published. The population parameters of amikacin in neonates, derived from the present study (i.e. coefficient for intraindividual variability and means ± SD for clearance and volume of distribution), can be applied to a further series of neonates to facilitate the prospective use of the bayesian method for individualizing amikacin dosage.

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“…Since the first experiences of PK, we realised the occurrence of a very large inter-patient variability of PK outcomes when the patients were treated with different clotting factor concentrates [13]. Anyway, the inter-occasions variability of each patient, when treated with the same concentrate, was lower [14]. This was a prerequisite for developing new strategy for treatment of haemophilia patients based on PK.…”

Section: Plasma-derived Clotting Factor Concentrates and Their Phamentioning

confidence: 99%

The History of Clotting Factor Concentrates Pharmacokinetics

Morfini¹

2017

JCM

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Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients’ home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak, and purification by Mabs made the plasma-derived concentrates safer and purer. CFCs were considered equivalent to the other drugs and general rules and methods of pharmacokinetics (PK) were applied to their study. After the first attempts by graphical methods and calculation of In Vivo Recovery, compartment and non-compartment methods were applied also to the study of PK of CFCs. The bioequivalence of the new concentrates produced by means of recombinant DNA biotechnology was evaluated in head-to-head PK studies. Since the beginning, the large inter-patient variability of dose/response of replacement therapy was realized. PK allowed tailoring haemophilia therapy and PK driven prophylaxis resulted more cost effective. Unfortunately, the need of several blood samples and logistic difficulties made the PK studies very demanding. Recently, population PK (PopPK) has been applied to the prediction of CFCs dosing by Bayesian methodology. By PopPK also sparse data may allow evaluating the appropriateness of replacement therapy.

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Multi-variate analysis of factors governing the pharmacokinetics of exogenous factor VIII in haemophiliacs

Cited by 42 publications

References 18 publications

Development and Small-Scale Production of a Severely Heated Factor VIII Concentrate

Development and Small-Scale Production of a Severely Heated Factor VIII Concentrate

Pharmacokinetics of Amikacin in Neonates

The History of Clotting Factor Concentrates Pharmacokinetics

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