Sharon J. Gardiner

Pharmacoeconomic Analyses of Azathioprine, Methotrexate and Prospective Pharmacogenetic Testing for the Management of Inflammatory Bowel Disease

AbstractObjectives: To compare the cost effectiveness of azathioprine (AZA), methotrexate (MTX) and no immunosuppression for maintaining remission of moderate to severe inflammatory bowel disease (IBD) in New Zealand Caucasians, and to determine whether prospective testing for poor metabolisers of AZA by genotype or phenotype is cost effective. Methods: Pharmacoeconomic models were developed to compare treatment costs and effects (QALYs) in theoretical populations of 1000 IBD patients over a 1-year period. Efficacy and tolerability profiles for AZA and MTX were taken from the literature. The costs (year 2004 values) of the drugs and treatment of adverse effects were estimated from New Zealand drug and service costs. Representations of the patients’ health-related quality of life (HR-QOL) were obtained from clinicians via the EQ-5D health state classification system and valued using the New Zealand EQ-5D social tariff. The effects of genotyping or phenotyping a population for thiopurine methyltransferase (TPMT) status were compared using the prevalence of TPMT deficiency in Caucasians, the relative risks of neutropenia and the associated costs. Results: Net cost savings (vs no immunosuppressant treatment) of approximately

Pharmacogenetic testing for drug metabolizing enzymes: is it happening in practice?

NZ2.5 million and

Rapid and simple high-performance liquid chromatographic assay for the determination of metformin in human plasma and breast milk.

NZ1 million were realised for AZA and MTX, respectively, for the theoretical 1000 patients, and AZA generated 877 QALYs compared with 633 for MTX. Phenotype and genotype testing generated net cost savings (vs no testing) of

Thiopurine Dose in Intermediate and Normal Metabolizers of Thiopurine Methyltransferase May Differ Three-Fold

NZ120 000 and

Transfer of metformin into human milk

NZ11 000, respectively. Savings related to phenotype tests were greater because of the lower assay costs of phenotype testing and a greater likelihood of pre-empting neutropenia. Conclusion: Our model suggests that both MTX and AZA may generate significant net cost savings and benefits for patients with IBD in New Zealand, with AZA likely to be more cost effective than MTX. Prospective testing for poor metabolisers of AZA may also be cost effective, with phenotype testing likely to be more cost effective than genotype testing.

Transfer of Risperidone and 9-Hydroxyrisperidone into Human Milk

It is widely claimed that pharmacogenetics may form the basis of ‘personalized medicine’. We sought to determine the current utilization of pharmacogenetic testing for drug metabolizing enzymes (DMEs). The hypothesis was that these tests were rarely performed clinically. Questionnaires were sent to 629 individuals representing laboratories, hospitals and universities throughout Australia and New Zealand. The questionnaires asked which facilities performed pharmacogenetic tests for selected DMEs, and details about the tests, if performed. The overall response rate was 81.1% (510/629); three respondents declined to participate. Clinical genotyping and phenotyping tests for DMEs could be performed by 10 (2.0% of 507) and 18 (3.6%) facilities, respectively. The most frequently performed genetic tests were for thiopurine methyltransferase (approximately 400 times in 2003) and pseudocholinesterase (approximately 250 times). The frequency of phenotyping exceeded genotyping by five- and eight-fold, respectively. One centre performed CYP2D6 phenotyping frequently (approximately 4200 times in 2003) for perhexiline. Genotyping and phenotyping tests for other cytochrome P450 enzymes, N-acetyltransferase-2 and dihydropyrimidine dehydrogenase were effectively never undertaken for clinical purposes. Pharmacogenetic tests for DMEs are currently performed rarely in clinical practice, despite repeated claims that they may benefit patient care. The only tests performed with any regularity in Australasia are for thiopurine methyltransferase and pseudocholinesterase, and CYP2D6 phenotyping in one centre for patients on perhexiline. The low clinical utilization reflects a poor evidence base, unestablished clinical relevance and, in the few cases with the strongest rationale, a slow translation to the clinical setting.

Breastfeeding during tacrolimus therapy

A rapid and simple high-performance liquid chromatographic (HPLC) assay for the determination of metformin in human plasma and breast milk is described. After proteins were precipitated with acetonitrile, metformin and the internal standard buformin were resolved on a cation-exchange column and detected by UV detection at 236 nm. Standard curves were linear over the concentration range 20.0-4000 microg/l. Intra- and inter-day coefficients of variation were <9.0% and the limit of quantification was around 20 microg/l.

Development and validation of a stereoselective liquid chromatography-tandem mass spectrometry assay for quantification of S- and R-metoprolol in human plasma

BACKGROUND & AIMS Patients with inflammatory bowel disease (IBD) may have different thiopurine dose requirements in relation to thiopurine methyltransferase (TPMT) genotype and/or phenotype. The purpose of this study was to determine thiopurine dose requirements in intermediate versus normal TPMT metabolism status. METHODS Consecutive patients starting azathioprine or 6-mercaptopurine for IBD were followed up for 9 months. The thiopurine dose was individualized using 6-thioguanine nucleotide (6-TGN) concentrations (range, 235-450 pmol/8 x 10(8) red blood cells [RBCs]) and clinical status. Additional assessments undertaken every three months included measures of disease activity. RESULTS Eight (10%) of 77 participants were withdrawn because of protocol violation. Fifty-two (75%) of the remaining 69 subjects ( approximately 90% and 10% with the TPMT*1/*1 and *1/*3 genotypes, respectively) completed follow-up on azathioprine (n = 46) or 6-mercaptopurine (n = 6). The mean initial dose (as azathioprine equivalents) was similar ( approximately 1 mg/kg/d) for the 2 TPMT genotypes, but after 9 months the dose was 50% lower in the TPMT*1/*3 group (0.9 vs 1.8 mg/kg/d, P < .0001). Despite dose adjustment, median 6-TGN concentrations still were 2-fold higher in the TPMT*1/*3 group at the end of the follow-up period (505 vs 273 pmol/8 x 10(8) RBCs, P = .02). This difference was 3-fold when the concentration was adjusted for dose (578 vs 183 pmol/8 x 10(8) per mg/kg/d, P = .0007). Results were similar if TPMT phenotype was used instead of genotype. Clinical outcomes did not differ between groups. CONCLUSIONS Initial target doses to attain therapeutic 6-TGN concentrations (>235 pmol/8 x 10(8) RBCs) in patients with IBD might be 1 and 3 mg/kg/d in intermediate and normal metabolizers, respectively.

Effect of pregnancy on the pharmacokinetics of metformin

Our objectives were to determine the milk‐to‐plasma ratio of metformin in lactating mothers and to estimate infant exposure.

Determination of celecoxib in human plasma and breast milk by high-performance liquid chromatographic assay.

OBJECTIVE To quantify the transfer of risperidone and its active metabolite 9-hydroxyrisperidone into breast milk, estimate the amount the infant receives, measure infant plasma concentrations, and clinically assess the safety of breast feeding during maternal risperidone administration. CASE SUMMARIES The transfer of risperidone and 9-hydroxyrisperidone into milk was studied in 2 breast-feeding women and one woman with risperidone-induced galactorrhea. Plasma samples were available from 2 of the women and from both breast-fed infants. The milk/plasma concentration ratio determined in 2 women was <0.5 for both compounds. The calculated relative infant “doses” were 2.3%, 2.8%, and 4.7% (as risperidone equivalents) of the maternal weight-adjusted doses. Risperidone and 9-hydroxyrisperidone were not detected in the plasma of the 2 breast-fed infants studied, and no adverse effects were noted. DISCUSSION Risperidone therapy is sometimes necessary in breast-feeding women, raising the issue of safety in the exposed infants. Our study shows that the relative infant dose is lower than the arbitrary 10% level of concern. The data provide clear guidance on infant exposure for the cases presented. CONCLUSIONS Maternal risperidone therapy is unlikely to be a significant hazard for the breast-fed infant in the short term. Nevertheless, decisions on whether a woman may breast-feed should be made as an individual risk-benefit analysis.