Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

AIM: To develop a population pharmacokinetic model for melphalan in children with malignant diseases and to evaluate limited sampling strategies for melphalan. METHODS: Melphalan concentration data following a single intravenous dose were collected from 59 children with malignant diseases aged between 0.3 and 18 years. The data were split into two sets: the model development dataset (39 children, 571 concentration observations) and the model validation dataset (20 children, 277 concentration observations). Population pharmacokinetic modelling was performed with the NONMEM software. Stepwise multiple linear regression was used to develop a limited sampling model for melphalan. RESULTS: A two-compartment model was fitted to the concentration-vs.-time data. The following covariate population pharmacokinetic models were obtained: (i) Clearance (l h(-1)) = 0.34.WT - 3.17.CPT + 0.0377.GFR, where WT = weight (kg), CPT = prior carboplatin therapy (0 = no, 1 = yes), and GFR = glomerular filtration rate (ml min(-1) 1.73 m(-2)); (ii) Volume of distribution (l) = 1.12 + 0.178.WT. Interpatient variability (coefficient of variation) was 27.3% for clearance and 33.8% for volume of distribution. There was insignificant bias and imprecision between observed and model-predicted melphalan concentrations in the validation dataset. A three-sample limited sampling model was developed which adequately predicted the area under the concentration-time curve (AUC) in the development and validation datasets. CONCLUSIONS: A population pharmacokinetic model for melphalan has been developed and validated and may now be used in conjunction with pharmacodynamic data to develop safe and effective dosing guidelines in children with malignant diseases.     

沙利度胺联合MP方案治疗老年多发性骨髓瘤临床观察

目的 观察沙利度胺联合MP方案(马法兰、强的松)与单用MP方案比较治疗老年多发性骨髓瘤(MM)的临床疗效及安全性.方法 治疗组(24例)口服沙利度胺,同时联合MP方案化疗,每月1个疗程.对照组(22例)单用MP方案化疗,马法兰、泼尼松的剂量和用法同治疗组.在4个疗程后,判断2组疗效及不良反应.结果 治疗组总有效率79....     

Linear pharmacokinetics: Calculation of the loading dose for two-compartment models with intermittent infusions

The problem of rapidly obtaining the steady state in long-term therapy by the use of a loading dose is formulated and solved for a linear two-compartment model. The general case of intermittent infusions is first considered; several choices of a loading dose are proposed. The results are then applied to the case of a continuous infusion and to multiple-bolus dosing regimens.     

The pharmacokinetics of melphalan in patients with multiple myeloma: An intravenous/oral study using a conventional dose regimen

The pharmacokinetics of melphalan have been studied after intravenous and oral dosing (10 mg) in 6 patients with multiple myeloma. After intravenous administration, mean plasma t0.5 alpha was 8.0 +/- 2.3 min, t0,5 beta was 63.3 +/- 8.7 min, and total systemic clearance was 510.4 +/- 57.9 ml/min. After oral administration, the drug was rapidly absorbed (lag-time = 18.4 +/- 3.7 min, absorption rate constant = 0.0547 +/- 0.0166 min-1, Tmax = 59.3 +/- 6.6 min), but there was considerable variation in its bioavailability (61.5 - 102.0% mean 78.3 +/- 6.3%). Variability in drug absorption may be responsible, at least in part, for variation in response to this drug.     

Pharmacokinetic drug evaluation of ixazomib citrate for the treatment of multiple myeloma

Introduction: multiple myeloma (MM) is a plasma cell disorder that represents the second most frequent hematologic cancer. Although MM is still an incurable disease, prognosis has improved in the last decades thanks to the introduction of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors.

Areas covered: ixazomib is the first oral PI recently approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in combination with lenalidomide and dexamethasone as salvage therapy in MM patients. In this paper, we focus on its pharmacokinetics features, as well as its safety and efficacy in clinical studies.

Expert opinion: ixazomib can be considered an oral analogue of bortezomib, with 9.5-day half-life, 58% of oral bioavailability, and a large distribution volume of 543L. These features make it a versatile molecule, potentially useful both in combination and as single agent. Oral route of administration and good efficacy/safety profile are its winning characteristics, providing the rationale for a future role also in the maintenance setting.     

Ceftriaxone pharmacokinetics following multiple intramuscular dosing

Summary The steady-state pharmacokinetics and tolerance of ceftriaxone after multiple i.m. doses of 0.5 and 1 g q12 h for 3.5 days were investigated in 12 healthy, adult volunteers. Ceftriaxone was rapidly absorbed after i.m. administration with mean peak times ranging from 1.3 to 1.9 h. Steady-state plasma concentrations were apparent after the third dose of both dosage regimens, with trough plasma concentrations of 24±6 and 39±8 µg/ml (mean±SD) after the 0.5 and 1 g q12 h regimens, respectively. Multiple i.m. administrations of ceftriaxone did not alter its elimination half-life; however, small increases were observed in the plasma clearance and volume of distribution at the 1-g regimen. These increases were attributed to the non-linear binding of ceftriaxone to human plasma proteins, and are therapeutically unimportant. Ceftriaxone was well tolerated and serious or lasting adverse reactions were not encountered in the study.     

New generation pharmacotherapy in elderly multiple myeloma patients

Background: Observational databases have demonstrated that the overall prognosis of multiple myeloma patients has markedly improved over the past decade, yet the greatest strides have been attained in younger rather than older patients. Objective: To review recent clinical trials that include new generation agents (thalidomide, lenalidomide and bortezomib) and autologous stem cell transplantation in older multiple myeloma patients. Results: Conventional regimens such as melphalan plus prednisone can be improved with the addition of thalidomide or bortezomib: more patients attain complete and near-complete remission, and progression-free survival rates are nearly doubled. In addition, autologous hematopoietic stem cell transplantation studies show that this treatment approach can be used successfully in selected older myeloma patients in whom the toxicity profile of autotransplant and resulting overall survival may be similar to that obtained in the younger patient group. Conclusions: In the advanced-age population, implementation of new therapies results in significant benefits in older as well as younger patients.     

Disposition of guanethidine during chronic oral therapy

Summary The plasma level and urinary excretion rate of guanethidine have been measured in 30 patients during oral maintenance therapy, and in 5 patients following discontinuation of therapy. A significant correlation was found between the daily average urinary excretion and the maintenance dose, although wide interindividual variation was noted among patients maintained on the same dose. A statistically significant correlation was also observed between the area under the plasma level curve during the dose interval and the oral maintenance dose. After discontinuation of chronic therapy, the half-life of 1.5 days of the initial phase of elimination was essentially in agreement with the half-life of almost 2 days determined in acute studies. In addition, a second phase of elimination with a half-life of 4 to 8 days was observed.Supported by Deutsche Forschungsgemeinschaft (He 791/4)     

The single and multiple dose pharmacokinetics of pranlukast in healthy volunteers

Objective: The pharmacokinetics of pranlukast, a leukotriene LTD₄ antagonist, were studied in 48 young, healthy subjects after single and repeated oral doses (given every 12 h) ranging from 112.5 to 675 mg. The doses were administered 30 minutes after a light breakfast. Results: Maximal drug concentrations generally occurred between 2 and 6 h after dosing, and there was some evidence of an absorption lag-time. Secondary peaks were observed in the plasma concentration vs. time profiles of many of the study subjects after both single and repeated doses, particularly during the period of maximum drug absorption. In general, after both single and repeated doses, there were related increases in the corresponding C_max and AUC with a rise in dose, although the increase was diminished at doses above 450 mg. With repeated dosing of pranlukast the mean AUC was generally higher (up to 1.6-fold), and the higher plasma concentrations allowed characterisation of a longer mean t_1/2 than after single dose administration. The mean steady-state trough plasma concentrations attained after evening doses were considerably higher (up to 14-fold) than those obtained after the morning dose. Conclusion: The data suggested that the pharmacokinetics of pranlukast are influenced by the time of dosing. Based on analysis of urinary 6β-hydroxycortisol excretion, there was no evidence that pranlukast modified the metabolic activity of cytochrome P-450 3A isoenzymes. Received: 6 November 1995/Accepted in revised form: 17 April 1996     

Ceftriaxone pharmacokinetics during peritoneal dialysis

Summary The purpose of this study was to investigate the pharmacokinetics of intraperitoneally (IP) administered ceftriaxone (CRO) in patients maintained on chronic peritoneal dialysis. A single 2 g dose of CRO was administered IP to six adult patients who did not have peritonitis at the time of study. After a 5 hour dwell, the peritoneal fluid was exchanged with CRO-free fluid. Exchanges were carried out every 4 to 8 h, over a 24- to 28-h period. The peak total plasma CRO concentration was 104 µg/ml. An average of 74.1% of the IP dose of CRO was absorbed. Plasma protein binding was nonlinear; mean free fraction ranged from 12.8 to 17.9% at low and high concentrations. Dialysate concentrations at the end of subsequent exchanges ranged from means of 19.9 to 2.9 µg/ml. Total CRO clearance from plasma was 10.1 ml·kg^–1·h^–1 and the mean terminal t_1/2 was 12.7 h. Dialytic clearance averaged 0.69 ml·kg^–1·h^–1, only 6.9% of total clearance. A model which incorporates known characteristics of CRO binding and distribution in anuric patients was used to simulate plasma and peritoneal concentrations of CRO during multiple dose IP drug administration.     

低剂量沙利度胺治疗多发性骨髓瘤致窦性心动过缓

患者男,62岁。因患多发性骨髓瘤IgA型ⅢA期,予以VTD(长春新碱、吡柔吡星和地塞米松)方案化疗4次。     

妊娠引起的药动学变化

妊娠使人体的生理发生变化,从而影响代谢酶活性和肾排泄能力,使药物的血浆浓度发生改变,因此需要调整药物剂量。本文从药物的吸收、分布、代谢和排泄4个方面概述了因妊娠而引起的药动学改变。     

美法仑衍生物的合成及其抗肿瘤活性研究

目的以苦参碱和18α-甘草次酸作为载体对美法仑进行结构拼合,并对其体内外抗肿瘤活性进行研究。方法以槐果碱和美法仑为原料,经过加成、酰化反应合成了美法仑衍生物2;以18α-甘草次酸和美法仑为原料,经酯化和酰化反应合成了美法仑衍生物5,目标化合物的结构经元素分析、MS、1H-NMR确证,并采用MTT法对其进行体外抗肿瘤活性研究,对体外活性较为显著的化合物2进行小鼠体内试验。结果目标化合物2和5的合成总收率分别为21.3%、18.1%。目标化合物2的体外抗肿瘤活性明显高于化合物5、18α-甘草次酸、苦参碱和美法仑。体内活性试验中,目标化合物2给药剂量为6、9μmol/kg时对Hep A肿瘤的抑瘤率分别为52.00%、62.12%,而6μmol/kg美法仑的抑制率为39.93%,化合物2的抑瘤效果优于美法仑,尤以高剂量效果最为明显。结论化合物2表现出体外、体内较高的抗肿瘤活性,值得进一步研究。     

Novel therapy in multiple myeloma

Treatment in patients with multiple myeloma remain to be defined. Younger patients (defined as a cut-off level < 65 years old) will be treated with chemotherapy and transplant procedures. However, most patients > 65 years old are not candidates for this therapeutic approach and the use of intensive chemotherapy could be associated to severe toxicity. We developed an new, not-cytotoxic regimen with dexamethasone 30 mg/m², iv, days 1 to 4, all trans retinoic acid 45 mg/m², po, days 5 to 14 and interferon alfa 2a 4.5 MU, sc, daily, days 5 to 14 (DAI regimen) administered every 28 days in number of 6 cycles, at this point patients were restaging, if they showed complete response, objective response or partial response they were conducted to received thalidomide 100–200 mg po, daily and dexamethasone 10 mg/2, po days 1 to 4 at monthly intervals, for 18 months. Forty one patients were enrolled in an Phase II study. In an intent to treat analysis all patients were evaluable. Complete response was observed in 18 cases (43%), objective response in 10 patients (24%) and partial response in 5 patients (12%), overall response rate was 80%. Eight patients were considered failures. At an median of 36 months, no relapse of progression disease has been observed, thus actuarial curves at 3-years showed that event free survival is 100% and overall survival is 91%. Toxicity was mild, all patients received the planned dose in time. This regimen appear to be useful in older patients with multiple myeloma, the response rate is higher and toxicity was mild. Controlled clinical trials comparing with conventional chemotherapy will be conducted to define the role of this therapeutic approach.     

The pharmacokinetics of low-dose thalidomide in Japanese patients with refractory multiple myeloma

Thalidomide has been used for the treatment of refractory multiple myeloma, the dosage in Japan is lower than in other countries; however, there is little information on the pharmacokinetics and their relationship with the drug response. The aim of this study was to characterize the pharmacokinetics of low-dose thalidomide in Japanese patients with refractory multiple myeloma, and to examine the relationship between pharmacokinetics and adverse events. On the first and second days, a 100 mg capsule was administered to 8 Japanese patients after breakfast and blood samples were obtained. The plasma concentrations were measured using HPLC and analyzed based on a one-compartment model. If intolerable adverse events were not observed for 14 d, the dose was increased to 200 mg. The average apparent volume of distribution (Vd/F), apparent total clearance (CL/F) and area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity), which were 45.3 l, 5.5 l/h and 21.7 microg.h/ml, respectively, with smaller Vd/F and CL/F and larger AUC0-infinity than in Caucasian populations. This pharmacokinetic difference may explain the dose difference between Japan and other countries. Adverse events were associated with AUC0-infinity, which was best correlated with plasma concentration at 12 h after administration. The 12-h time point was suggested to be a capable indicator for "safety-oriented" therapeutic drug monitoring of thalidomide.     

Melphalan: old and new uses of a still master drug for multiple myeloma

The treatment of multiple myeloma has seen significant changes from the initial use of melphalan to the introduction of stem cell transplantation and, most recently, to the era of novel targeted agents. Melphalan still remains as a reference drug for combination regimens, including emerging newer therapeutic options, either used at a standard dose for initial or salvage treatments in patients who are not eligible for more intensive therapies, or in conjunction with new molecules within high-dose chemotherapy programs. In this review, the authors analyze old and novel regimens, including melphalan for the treatment of newly diagnosed or relapsed/resistant patients with multiple myeloma in the clinical settings of standard chemotherapy, as well as autologous or allogeneic stem cell transplantation.     

Results of the first bortezomib-based induction therapy in the treatment of multiple myeloma

This is a comment on the IFM 2005 – 01 Phase III trial that compared, for the first time, the efficacy and the safety of a bortezomib-containing induction regimen with conventional chemotherapy before autologous stem-cell transplantation in multiple myeloma (MM) patients. Between 2005 and 2008, 482 patients were randomized to vincristin/doxorubicin/dexamethasone (VAD), VAD + dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) consolidation, bortezomib + dexamethasone and bortezomib + dexamethasone + DCEP consolidation followed by autologous stem-cell transplantation. The trial was conducted in 89 sites in France, Belgium and Switzerland. The novel agent-based induction therapy (bortezomib/dexamethasone) achieved higher complete remission (CR)/nearCR rates, as well as less treatment-related mortality, but higher rates of polyneuropathy than the conventional chemotherapy-based induction therapy (VAD/VAD + DCEP). The difference in progression-free survival (PFS) difference was not statistically significant but a trend to longer PFS was seen to favor to the bortezomib-containing regimen; bortezomib and dexamethason (BD) was, therefore, proposed to be a standard of care by the authors of the study.