1.
Wallin, Johan E., et al.
(författare)
A tool for neutrophil guided dose adaptation in chemotherapy
2009
Ingår i: Computer Methods and Programs in Biomedicine. - : Elsevier BV. - 0169-2607 .- 1872-7565. ; 93:3, s. 283-291
Tidskriftsartikel (refereegranskat) abstract
Chemotherapy dosing in anticancer treatment is a balancing act between achieving concentrations that are effective towards the malignancy and that result in acceptable side-effects. Neutropenia is one major side-effect of many antitumor agents, and is related to an increased risk of infection. A model capable of describing the time-course of myelosuppression from administered drug could be used in individual dose selection. In this paper we describe the transfer of a previously developed semi-mechanistic model for myelosuppression from NONMEM to a dosing tool in MS Excel, with etoposide as an example. The tool proved capable to solve a differential equation system describing the pharmacokinetics and pharmacodynamics, with estimation performance comparable to NONMEM. In the dosing tool the user provides neutrophil measures from a previous treatment course and request for the dose that results in a desired nadir in the upcoming course through a Bayesian estimation procedure.
2.
de Jong, F. A., et al.
(författare)
Irinotecan-induced diarrhea : functional significance of the polymorphic ABCC2 transporter protein
2007
Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 81:1, s. 42-49
Tidskriftsartikel (refereegranskat) abstract
Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04–0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49–7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.
3.
Friberg, Lena E, et al.
(författare)
Mechanistic models for myelosuppression
2003
Ingår i: Investigational new drugs. - 0167-6997 .- 1573-0646. ; 21:2, s. 183-194
Tidskriftsartikel (refereegranskat) abstract
As myelosuppression is the dose-limiting toxicity for most chemotherapeutic drugs, modelers attempt to find relationships between drug and toxicity to optimize treatment. Mechanistic models, i.e. models based on physiology and pharmacology, are preferable over empirical models, as prior information can be utilized and as they generally are more reliable for extrapolations. To account for different dosing-regimens and possible schedule-dependent effects, the whole concentration-time profile should be used as input into the pharmacokinetic-pharmacodynamic model. It is also of importance to model the whole time course of myelosuppression to be able to predict both the degree and duration of toxicity as well as consecutive courses of therapy. A handful of (semi)-mechanistic pharmacokinetic-pharmacodynamic models with the above properties have been developed and are reviewed. Ideally, a model of myelosuppression should separate drug-specific parameters from system related parameters to be applicable across drugs and useful under different clinical settings. Introduction of mechanistic models of myelosuppression in the design and evaluation of clinical trials can guide in the decision of optimal sampling times, contribute to knowledge of optimal doses and treatment regimens at an earlier time point and identify sub-groups of patients at a high risk of myelosuppression.
4.
Friberg, Lena E
(författare)
Pharmacokinetic-Pharmacodynamic Modelling of Anticancer Drugs : Haematological Toxicity and Tumour Response in Hollow Fibres
2003
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Established quantitative relationships between dose, plasma concentrations and response [pharmacokinetic-pharmacodynamic (PKPD) models] have a high potential in improving therapeutic indices of anticancer drug therapy and in increasing drug development efficiency. PKPD modelling is a helpful tool for characterising and understanding schedule dependence. The aim of this thesis was to develop PKPD models of anticancer drugs for tumour effects and haematological toxicity, which is the most frequent dose-limiting toxicity.PK and haematological toxicity after several schedules were studied in rats and semi-physiological PKPD models for the whole time course of myelosuppression were developed from animal and patient data. The possibility to implant hollow fibres filled with tumour cells in immunocompetent rats was investigated for simultaneous assessment of PK, tumour response and haematological toxicity. Population data analyses were performed using the software NONMEM. When all injections were administered within eight hours, fractionated schedules of 5-fluorouracil and epirubicin produced similar haematological toxicity in rats as a single dose, when the non-linear PK of 5-fluorouracil was accounted for. When the time interval was extended to two days for 5-fluorouracil, the fractionated regimens were more toxic. The developed semi-physiological PKPD models included transit compartments that mimic maturation stages in bone marrow and explain the time lag. Feedback mechanisms characterised the rebound. The models successfully described myelosuppression in patients (DMDC) and rats (5-fluorouracil), after different administration schedules. Further developments made it possible to characterise the time course of myelosuppression after administration of each one of six different drugs, with parameters related to the haematopoietic system consistent across drugs. The developed hollow fibre model in immunocompetent rats was successfully applied to monitor PK, toxicity and the time course of antitumour effects. PKPD modelling illustrated that the schedule dependence of the anticancer agent CHS 828 is partly due to dose-dependent bioavailability and partly due to a schedule-dependent PD effect.
5.
Hennig, Stefanie, et al.
(författare)
Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients
2006
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 45:11, s. 1099-1114
Tidskriftsartikel (refereegranskat) abstract
Objective: The objective of the study was to characterise the population pharmacokinetic properties of itraconazole and its active metabolite hydroxyitraconazole in a representative paediatric population of cystic fibrosis and bone marrow transplant (BMT) patients and to identify patient characteristics influencing the pharmacokinetics of itraconazole. The ultimate goals were to determine the relative bioavailability between the two oral formulations (capsules vs oral solution) and to optimise dosing regimens in these patients. Methods: All paediatric patients with cystic fibrosis or patients undergoing BMT at The Royal Children's Hospital, Brisbane, QLD, Australia, who were prescribed oral itraconazole for the treatment of allergic bronchopulmonary aspergillosis (cystic fibrosis patients) or for prophylaxis of any fungal infection (BMT patients) were eligible for the study. Blood samples were taken from the recruited patients as per an empirical sampling design either during hospitalisation or during outpatient clinic visits. ltraconazole and hydroxy-itraconazole plasma concentrations were determined by a validated high-performance liquid chromatography assay with fluorometric detection. A nonlinear mixed-effect modelling approach using the NONMEM software to simultaneously describe the pharmacokinetics of itraconazole and its metabolite. Results: A one-compartment model with first-order absorption described the itraconazole data, and the metabolism of the parent drug to hydroxy-itraconazole was described by a first-order rate constant. The metabolite data also showed one-compartment characteristics with linear elimination. For itraconazole the apparent clearance (CLitraconazole) was 35.5 L/hour, the apparent volume of distribution (V-d(itraconazole)) was 672L, the absorption rate constant for the capsule formulation was 0.0901 h(-1) and for the oral solution formulation was 0.96 h-1. The lag time was estimated to be 19.1 minutes and the relative bioavailability between capsules and oral solution (F-rel) was 0.55. For the metabolite, volume of distribution, V-m/(F (.) f(m)), and clearance, CL/(F (.) fm), were 10.6L and 5.28 L/h, respectively. The influence of total bodyweight was significant, added as a covariate on CLitraconazoie/F and V-d(itraconazole)/F (standardised to a 70kg person) using allometric three-quarter power scaling on CLitraconazole/F, which therefore reflected adult values. The unexplained between-subject variability (coefficient of variation %) was 68.7%, 75.8%, 73.4% and 61.1% for CLitraconazoie/F, Vd(itraconazole)/F, CLm/(F (.) fm) and F-rel, respectively. The correlation between random effects of CLitraconazole and Vd((itraconazole)) was 0.69. Conclusion: The developed population pharmacokinetic model adequately described the pharmacokinetics of itraconazole and its active metabolite, hydroxy-itraconazole, in paediatric patients with either cystic fibrosis or undergoing BMT. More appropriate dosing schedules have been developed for the oral solution and the capsules to secure a minimum therapeutic trough plasma concentration of 0.5 mg/L for these patients.
6.
Isbister, Geoffrey K., et al.
(författare)
Activated charcoal decreases the risk of QT prolongation after citalopram overdose
2007
Ingår i: Annals of Emergency Medicine. - : Elsevier BV. - 0196-0644 .- 1097-6760. ; 50:5, s. 593-600
Tidskriftsartikel (refereegranskat) abstract
Study objective: We determine whether single-dose activated charcoal (SDAC) administration after citalopram overdose reduces the proportion of patients developing abnormal QT prolongation. Methods: Data were collected retrospectively for citalopram overdose patients presenting to 8 emergency departments. Demographics, dose, coingested drugs, SDAC administration, and serial ECGs were extracted from medical records. The primary outcome was the proportion of patients who had an observed QT,RR combination at any time above an abnormal threshold, established as a predictor of torsade de pointes. We compared the proportion of patients with QT prolongation who received or did not receive SDAC. These data were analyzed within a Bayesian framework, using probabilities of abnormal QT,RR combinations with and without derived from a previous single-center study. WinBUGS was used to generate posterior estimates and credible intervals of the relative risk by combining the prior probabilities and the study data. Results: SDAC was administered on average 2.1 hours (range, 0.5 to 6.25 hours) after ingestion in 48 of 254 admissions, and abnormal QT,RR combinations occurred in 2 cases (4.2%), compared with 23 of 206 (11.2%) cases not receiving SDAC. There did not appear to be any clinically important difference in age, sex, dose, and cardiotoxic coingestants between the 2 groups. No cases of torsade de pointes occurred. The estimated relative risk of having an abnormal QT,RR combination for SDAC compared to no SDAC was 0.28 (0.06 to 0.70) (median with 2.5% and 97.5% credible limits). The probability that the relative risk was less than 1.0 was 0.99, which can be interpreted as very strong evidence in favor of a beneficial effect of SDAC. The absolute risk difference was estimated as 7.5% and the median number needed to treat as 13.3. Conclusion: SDAC may be effective in reducing the risk of a prolonged QT in patients after citalopram overdose. Current trends toward nonuse of activated charcoal should be evaluated to determine whether patients poisoned by specific agents may benefit from activated charcoal administration.
7.
8.
Isbister, Geoffrey K, et al.
(författare)
Human methyl parathion poisoning
2007
Ingår i: Clinical Toxicology. - : Informa UK Limited. - 1556-3650 .- 1556-9519. ; 45:8, s. 956-960
Tidskriftsartikel (refereegranskat) abstract
Background. Methyl parathion is classed as an extremely hazardous pesticide with a rodent LD50 of 6 to 24 mg/kg. It has been banned in numerous countries, but there are few reports of acute methyl parathion poisoning. Methods. Plasma cholinesterase and acetylcholinesterase were measured in blood. Methyl parathion and the major metabolite 4-nitrophenol where measured in serum and urine. Based on the available concentration-time data, the pharmacokinetic parameters of methyl parathion were estimated for this patient. Case Report and Results. A 29-year-old male ingested 50 to 100mL (12 to 24 g) of methyl parathion causing delayed and prolonged suppression of acetylcholinesterase but almost no clinical effects. Absorption was predicted to last for 30 hours and the bioavailability appeared to be very low. Conclusions. Although it is feasible the patient ingested much less, a tenth of his alleged ingestion dose is more than the oral LD50 in rats. Methyl parathion appears to be less toxic in humans than parathion for similar amounts ingested, which is not consistent with the two pesticides having similar rodent LD50.
9.
10.
Jansson, Britt, et al.
(författare)
Quantitative analysis of colistin A and colistin B in plasma and culture medium using a simple precipitation step followed by LC/MS/MS
2009
Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 49:3, s. 760-767
Tidskriftsartikel (refereegranskat) abstract
An analytical method for quantitation of colistin A and colistin B in plasma and culture medium is described. After protein precipitation with acetonitrile (ACN) containing 0.1% trifluoroacetic acid (TFA), the supernatants were diluted with 0.03% TFA. The compounds were separated on an Ultrasphere C18 column, 4.6 mm x 250 mm, 5 mu m particle size with a mobile phase consisting of 25% ACN in 0.03% TFA and detected with tandem mass spectrometry. The instrument was operating in ESI negative ion mode and the precursor-product ion pairs were m/z 1167.7 -> 1079.6 for colistin A and m/z 1153.7 -> 1065.6 for colistin B. The lower limit of quantification (LLOQ) for 100 mu L plasma was 19.4 and 10.5 ng/mL for colistin A and B, respectively, with CV <6.2% and accuracy <+/- 12.6%. For culture medium (50 mu L+ 50 mu L plasma), LLOQ was 24.2 and 13.2 ng/mL for colistin A and B, respectively, with CV <11.4% and accuracy <+/- 8.1%. The quick sample work-up method allows for determination of colistin A and B in clinical samples without causing hydrolysis of the prodrug colistin methanesulfonate (CMS).
