Summary We analysed 1221 serum activity measurements in 168 children from the Berlin‐Frankfürt‐Münster acute lymphoblastic leukaemia studies, ALL‐BFM (Berlin‐Frankfürt‐Münster) 95 and ALL‐BFM REZ, in order to develop a pharmacokinetic model describing the activity‐time course of pegylated (PEG)‐asparaginase for all dose levels. Patients received 500, 750, 1000 or 2500 U/m2 PEG‐asparaginase on up to nine occasions. Serum samples were analysed for asparaginase activity and data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. VI, Globomax, Hanouet, MD, USA). Different linear and nonlinear models were tested. The best model applicable to all dosing groups was a one‐compartmental model with clearance (Cl) increasing with time according to the formula: Cl=Cli *e(0·0793 *t) where Cli = initial clearance and t = time after dose. The parameters found were: volume of distribution (V) 1·02 ± 26% l/m2, Cli 59·9 ± 59% ml/d per m2 (mean ± interindividual variability). Interoccasion variability was substantial with 0·183 l/m2 for V and 44·7 ml/d per m2 for Cl, respectively. A subgroup of the patients showed a high clearance, probably due to the development of inactivating antibodies. This is the first model able to predict the activity‐time course of PEG‐asparaginase at different dosing levels and can therefore be used for developing new dosing regimens.

Purpose: To evaluate plasma cystatin level as a covariate to predict topotecan pharmacokinetics.Cystatin C, a member of the cystatin superfamily of cysteine proteinase inhibitors, has been recently proposed as an alternative endogenous marker of glomerular filtration. Renal function is known as a key factor of topotecan clearance. Experimental Design: Data were obtained from 59 patients who underwent drug monitoring for individual dosing of topotecan. Topotecan plasma concentrations versus time were analyzed using a nonlinear mixed effect model according to a two-compartment pharmacokinetic model and a first-order conditional estimation method. A proportional error model was used for residual and interpatient variabilities. Data-splitting was done randomly to create a model-building data set (44 patients) and a model validation data set (15 patients).Results: Using the building data set, four covariates significantly decreased the objective function value and interindividual variability on topotecan clearance (CL) when tested individually: ideal body weight (IBW), serum creatinine, age, and cystatin C level. The best model was: CL (L/hour) = 20.2 [cystatin C (mg/L) / 1.06] À0.60 [IBW (kg) / 57] 0.95 . Prospective evaluation using the validation data set confirmed that the model based on cystatin C had a better predictive value than the models based on serum creatinine or body surface area. Conclusion: Cystatin C is a marker of drug elimination which is superior to serum creatinine for topotecan. It deserves to be further explored as a promising covariate for drug dosing as well as selection criteria for clinical studies of drugs eliminated mainly or partially by the kidney.

EGR cooling is a worthwhile technology capable of reducing NOx-emissions and increasing the efficiency of CI engines. Challenges arise when low-temperature cooling is applied with high fuel sulfur contents. The resulting sulfuric acid condenses in conjunction with the water of the exhaust gas and gives rise to corrosion of coolers and engine components. Additionally, fouling of the EGR cooler is exacerbated by the condensation of acidic components compromising EGR performance. In order to gain a better understanding of the underlying processes a combined experimental and model-based approach is presented. Tests of two different EGR-cooler concepts under various conditions showed a strong influence of the fuel sulfur content on fouling and condensation. The one-dimensional cooler model developed alongside these experiments consists of an activity coefficient model (NRTL) of the binary system water -sulfuric acid and a condensation model that allows for simulating the coupled condensation of both vapor components. Comparison of experimental fouling and simulated condensation results show good agreement in interpreting critical fouling phenomena that occur at temperatures in between the acid-water dew point and the dew point of pure water.

Continuing the studies on photoaffinity labelled analogues of the peptide hormone bradykinin (BK), several labelled antagonists were synthesized and characterized regarding their biological activities on rat uterus (RUT) and guinea pig ileum (GPI). The photoreactive amino acid p-benzoyl-phenylalanine (Bpa) was incorporated in potent, iodinated BK analogues at positions -2, -1, 0 and 7. The newly synthesized BK antagonists were derived from HOE 140 ([DArg0, Hyp3, Thi5, D-Tic7, Oic8]-BK) or [D-Phe7]-BK. Because the application of Bpa requires an additional group for the introduction of 125I, iodinated tyrosine was inserted at different positions as a model for radioiodination. Suitable positions for incorporation of tyrosine residues are -1, 0, 3 and 7, whereas the compound with 3-I-Tyr at position 4 had only a low biological activity. The antagonists obtained by modification of HOE 140 generally retained a high antagonistic potency. In this group [D-Bpa-2, 3-I-D-Tyr-1, D-Arg0, Hyp3, Thi5, D-Tic7, Oic8]-BK (pA2 values 8.06 on RUT and 8.15 on GPI) and [Bpa-1, D-Arg0, 3-I-Tyr3, Thi5, D-Tic7, Oic8]-BK (pA2 values 7.55 on RUT and 8.07 on GPI) belong to the most active compounds. The incorporation of D-Bpa at position 7 also resulted in potent analogues. The antagonists [3-I-Tyr-1, D-Arg0, D-Bpa7]-BK (pA2 on RUT 7.69) and [3-I-Tyr-1, D-Arg0, D-Bpa7, Oic8]-BK (pA2 on GPI 7.53) are an alternative to the N-terminal modified HOE 140 analogues. Compounds with D-Bpa7 act as pure competitive antagonists, whereas the HOE 140 derivatives show a mixed antagonism. The comparison of the results between photoaffinity labelled agonists and antagonists suggests that modifications in the series of BK antagonists were better tolerated.

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