Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model

AIMS: Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk

Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 × 10 −5 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10 −4 ; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 × 10 −4 ; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN

60歳以上の造血器悪性腫瘍に対して施行した臍帯血移植の3例

(症例1)68歳男性.2002年12月に発症したmantle cell lymphoma,clinical stage III A.CHOP療法,rituximab-CHOP療法により完全寛解となった.治療中に直腸癌が認められたため手術を施行した.その後頚部再発をきたし,化学療法,放射線局所照射を行ったが寛解には到らず,2004年4月に,膀帯血移植を施行した.Day19に生着,day28に完全キメラを確認した.Day44に頚部再発を認め,FK506中止し,腫瘍は縮小となったが再び増大し,化学療法を施行中である.(症例2)62歳男性.2002年7月に発症した.myelodysplastic syndrome (MDS) refractory anemia with excess of blasts(RAEB).Acute myeloblastic leukemia(AML)への進展を認めたため2004年5月に膀帯血移植を施行した.Day31に生着,day28に完全キメラを確認した.現在完全寛解を維持している.(症例3)60歳女性.2004年6月に発症したMDS(RAEB in transformation).早々にAMLへ移行したため,PS1で2004年8月に臍帯血移植を施行した.Day78に生着,day28に完全キメラを確認した.Day61に皮膚stage3・grade IIのacute graft versus host diseaseが出現したが,predonisolone 0.5mg/kg開始し速やかに消退した.現在完全寛解を維持している.最近施行されるようになってきた高齢者に対する造血幹細胞移植は,患者の高齢化に伴い健常な同胞ドナー候補を探すことが困難であり,また病勢によっては骨髄バンクからドナー候補を探す時間的な余裕がないことなどが問題となっている.一方,膀帯血移植は当初は小児領域で施行されていたが,最近では主に成人に対して施行されるようになっている.今回60歳以上の高齢者の造血器悪性腫瘍3例に対して臍帯血移植を施行し,その経過,合併症について検討した.高齢者の造血器悪性腫瘍に対して移植を考慮する場合に同胞に適するドナーがいない場合,非血縁骨髄移植のみならず,今後は臍帯血移植も選択肢の一つとして考慮し得るということが示された.Allogenic stem cell transplantation is now done not only for younger but also for elderly patients. It is very difficult for elderly patients to find healthy, suitable related donors, and in many cases there is not enough time to find unrelated bone marrow donors due to disease status. Cord blood transplantation was originally done for pediatric patients, but is now done for more adult patients than pediatric patients. We performed cord blood transplantation for 3 patients over 60 years old with hematological malignancies. We report their clinical courses and complications. If there are no suitable related donors for elderly patients, it is possible to choose not only unrelated bone marrow transplantation, but also cord blood transplantation

Relative bioequivalence of amoxicillin dissolved in breast milk

BACKGROUND: Oral antibiotics use in infants in developing countries is challenging because liquid formulations are often unavailable. However, dissolving solid formulation of drugs in water poses a risk of gastrointestinal infection. Although mother's milk may be a potential vehicle, no evidence exists to indicate that antibiotics dissolved in human milk are bioequivalent to those dissolved in water. Therefore, we compared pharmacokinetic parameters of an orally administered antibiotic, amoxicillin, dissolved in human milk, to those of water-dissolved amoxicillin. METHODS: A pharmacokinetic study was conducted in 16 healthy adult volunteers in a randomised crossover design. Marketed amoxicillin powder for suspension was dissolved in either human milk or water at a final concentration of 50 mg/mL, and 10 mL was given orally in a fasting state. Timed blood samples were obtained and plasma amoxicillin was quantified using liquid chromatography-mass spectrometry. FINDINGS: Results showed that pharmacokinetic parameters, including area-under-the-curve, Cmax and half-life of the water-based and milk-based amoxicillin administration were not significantly different. 90% CIs of the ratios of these parameters in concomitant breast milk administration to those of water were within 89% and 116%, suggesting they are bioequivalent (defined as a range between 80% and 125%). INTERPRETATION: We conclude that oral administration of amoxicillin dissolved in human milk at 50 mg/mL results in pharmacokinetics profiles comparable to amoxicillin dissolved in water. Pharmaceutical interactions between amoxicillin and breast milk are unlikely, suggesting no need to modify dosing schedules.Fil: Yazdani Brojeni, Parvaneh. University Of Toronto. Hospital For Sick Children; CanadáFil: García Bournissen, Facundo. University Of Toronto. Hospital For Sick Children; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fujii, Hisaki. University Of Toronto. Hospital For Sick Children; CanadáFil: Tanoshima, Reo. University Of Toronto. Hospital For Sick Children; CanadáFil: Ito, Shinya. University Of Toronto. Hospital For Sick Children; Canad

Thiopurine Dosing using Thiopurine Methyltransferase Status: A Systematic Review of Clinical Guidance

Produced by Technology Assessment at SickKids, Hospital for Sick Children.The objective of this study was to conduct a systematic review of clinical guidance documents that recommend TPMT testing prior to the administration of thiopurine drugs. The specific aims were to 1) review the breadth of guidance documents and their sources, and 2) critically appraise the quality of the guidance documents by evaluating the quality of evidence used to support the preferential use of one method (genotyping versus phenotyping) over another and used to guide dose adjustments based on TPMT status.Supported by a program grant from the Ontario Ministry of Health and Long-Term Care Drug Innovation Fun

Clinical Courses of Two Pediatric Patients with Acute Megakaryoblastic Leukemia Harboring the CBFA2T3-GLIS2 Fusion Gene

Acute megakaryoblastic leukemia (AMKL) in children without Down syndrome (DS) has an extremely poor outcome with 3-year survival of less than 40%, whereas AMKL in children with DS has an excellent survival rate. Recently, a novel recurrent translocation involving CBFA2T3 and GLIS2 was identified in about 30% of children with non-DS AMKL, and the fusion gene was reported as a strong poor prognostic factor in pediatric AMKL. We report the difficult clinical courses of pediatric patients with AMKL harboring the CBFA2T3-GLIS2 fusion gene

Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

10.1002/cpt.1179CLINICAL PHARMACOLOGY & THERAPEUTICS1052402-41