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Modelling of patient EMS exposure: translating pharmacokinetics of EMS in vitro and in animals into patients.
Toxicol Lett. 2009 Nov 12; 190(3):310-6.TL

Abstract

In order to support the toxicological risk assessment for the ethyl methanesulfonate (EMS) exposure of patients ingesting contaminated Viracept tablets (Müller and Singer, 2009), there was a need to correlate the effects observed in in vivo genotoxicity studies with mice to EMS exposure and to estimate human exposure to EMS at the level of contamination of Viracept tablets. The species differences in volume of distribution of EMS, a key factor for determination of its C(max), were small in the species investigated (mouse, rat, monkey), the species differences in clearance, the key factor involved in AUC assessment, were large (Lavé et al., 2009). Because of this uncertainty in extrapolation of clearance across species we used a conservative approach for human exposure predictions in terms of AUC where clearance was assumed to solely reflect the chemical stability of EMS neglecting additional clearance pathways such as metabolism and exhalation. This approach was compared to the estimates obtained from allometric scaling based on rat clearance, the species leading to the lowest clearance predicted in man. We found that both approaches led to nearly identical predictions of the human AUC. Thus, we predict a human AUC of 13 microM h for patients ingesting the most contaminated Viracept tablets, corresponding to a maximal daily intake of 0.055 mg/kg of EMS. The C(max) of EMS in these patients is predicted to be 0.85 microM. In order to provide a basis for toxicological risk assessment, these maximal human AUC and C(max) values are to be compared to the AUC and C(max) values in mice at the EMS dose of 25mg/kg which was found to be the threshold dose for induction of mutagenic effects, i.e. the dose at which no mutagenic effects were observed (Gocke et al., 2009-a). We calculate AUC and C(max) in mice at the threshold dose to be 350 microM h and 315 microM, respectively. Thus we conclude that a large safety factor can be deduced, whatever the basis of comparison, as is discussed in detail by Müller et al. (2009).

Authors+Show Affiliations

Non-Clinical Safety and Drug Metabolism and Pharmacokinetics Departments, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland. thierry.lave@roche.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19695316

Citation

Lavé, Thierry, et al. "Modelling of Patient EMS Exposure: Translating Pharmacokinetics of EMS in Vitro and in Animals Into Patients." Toxicology Letters, vol. 190, no. 3, 2009, pp. 310-6.
Lavé T, Paehler A, Grimm HP, et al. Modelling of patient EMS exposure: translating pharmacokinetics of EMS in vitro and in animals into patients. Toxicol Lett. 2009;190(3):310-6.
Lavé, T., Paehler, A., Grimm, H. P., Gocke, E., & Müller, L. (2009). Modelling of patient EMS exposure: translating pharmacokinetics of EMS in vitro and in animals into patients. Toxicology Letters, 190(3), 310-6. https://doi.org/10.1016/j.toxlet.2009.07.031
Lavé T, et al. Modelling of Patient EMS Exposure: Translating Pharmacokinetics of EMS in Vitro and in Animals Into Patients. Toxicol Lett. 2009 Nov 12;190(3):310-6. PubMed PMID: 19695316.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modelling of patient EMS exposure: translating pharmacokinetics of EMS in vitro and in animals into patients. AU - Lavé,Thierry, AU - Paehler,Axel, AU - Grimm,Hans Peter, AU - Gocke,Elmar, AU - Müller,Lutz, Y1 - 2009/08/18/ PY - 2009/03/23/received PY - 2009/07/20/revised PY - 2009/07/27/accepted PY - 2009/8/22/entrez PY - 2009/8/22/pubmed PY - 2009/11/11/medline SP - 310 EP - 6 JF - Toxicology letters JO - Toxicol Lett VL - 190 IS - 3 N2 - In order to support the toxicological risk assessment for the ethyl methanesulfonate (EMS) exposure of patients ingesting contaminated Viracept tablets (Müller and Singer, 2009), there was a need to correlate the effects observed in in vivo genotoxicity studies with mice to EMS exposure and to estimate human exposure to EMS at the level of contamination of Viracept tablets. The species differences in volume of distribution of EMS, a key factor for determination of its C(max), were small in the species investigated (mouse, rat, monkey), the species differences in clearance, the key factor involved in AUC assessment, were large (Lavé et al., 2009). Because of this uncertainty in extrapolation of clearance across species we used a conservative approach for human exposure predictions in terms of AUC where clearance was assumed to solely reflect the chemical stability of EMS neglecting additional clearance pathways such as metabolism and exhalation. This approach was compared to the estimates obtained from allometric scaling based on rat clearance, the species leading to the lowest clearance predicted in man. We found that both approaches led to nearly identical predictions of the human AUC. Thus, we predict a human AUC of 13 microM h for patients ingesting the most contaminated Viracept tablets, corresponding to a maximal daily intake of 0.055 mg/kg of EMS. The C(max) of EMS in these patients is predicted to be 0.85 microM. In order to provide a basis for toxicological risk assessment, these maximal human AUC and C(max) values are to be compared to the AUC and C(max) values in mice at the EMS dose of 25mg/kg which was found to be the threshold dose for induction of mutagenic effects, i.e. the dose at which no mutagenic effects were observed (Gocke et al., 2009-a). We calculate AUC and C(max) in mice at the threshold dose to be 350 microM h and 315 microM, respectively. Thus we conclude that a large safety factor can be deduced, whatever the basis of comparison, as is discussed in detail by Müller et al. (2009). SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/19695316/Modelling_of_patient_EMS_exposure:_translating_pharmacokinetics_of_EMS_in_vitro_and_in_animals_into_patients_ DB - PRIME DP - Unbound Medicine ER -