A rational approach to drug therapy of type 2 diabetes mellitus

Several new pharmacological agents have recently been developed to optimise the management of type 2 (non-insulin-dependent) diabetes mellitus. The aim of this article is to briefly review the various therapeutic agents available for management of patients with type 2 diabetes mellitus and to suggest a potential approach to drug selection. There are three general therapeutic modalities relevant to diabetes care. The first modality is lifestyle adjustments aimed at improving endogenous insulin sensitivity or insulin effect. This can be achieved by increased physical activity and bodyweight reduction with diet and behavioural modification, and the use of pharmacological agents or surgery. This first modality is not discussed in depth in this article. The second modality involves increasing insulin availability by the administration of exogenous insulin, insulin analogues, sulphonylureas and the new insulin secretagogue, repaglinide. The most frequently encountered adverse effect of these agents is hypoglycaemia. Bodyweight gain can also be a concern, especially in patients who are obese. The association between hyperinsulinaemia and premature atherosclerosis is still a debatable question. The third modality consists of agents such as biguanides and thiazolidinediones which enhance insulin sensitivity, or agents that decrease insulin requirements like the alpha-glucosidase inhibitors. Type 2 diabetes mellitus is a heterogeneous disease with multiple underlying pathophysiological processes. Therapy should be individualised based on the degree of hyperglycaemia, hyperinsulinaemia or insulin deficiency. In addition, several factors have to be considered when prescribing a specific therapeutic agent. These factors include efficacy, safety, affordability and ease of administration.     

Biochemical monitoring of patients treated with antihypertensive therapy for adverse drug reactions: a systematic review

Biochemical monitoring of patients treated with antihypertensive therapy is recommended in order to identify potential adverse reactions to treatment. We aimed to review the literature investigating the nature of biochemical monitoring in adults treated in primary care with antihypertensive drugs. Specifically, we wished to establish (i) the proportion of patients with biochemical baseline testing prior to the initiation of antihypertensive therapy; (ii) the proportion of patients with biochemical monitoring after initiation of antihypertensive therapy; (iii) the patient characteristics associated with biochemical monitoring; (iv) the frequency of biochemical monitoring after the initiation of antihypertensive therapy; and (v) the relationship, if any, between biochemical monitoring and adverse patient outcomes. We searched MEDLINE, EMBASE and Google Scholar from 1948 to 31 December 2010 using a combination of text words and search terms. Retrospective and prospective cohort studies, cross-sectional studies, randomized controlled trials or quasi-randomized controlled trials, and audits of current clinical practice were included. Clinical trials, case reports and case series were excluded. Studies were included if they provided data on the proportion of patients treated with antihypertensive therapy in primary care who had any biochemical monitoring before or after the initiation of therapy. In total, 15 studies were included in our review, which used a wide variety of definitions of monitoring prior to and after the initiation of antihypertensive therapy. From 17% to 81% of patients treated with antihypertensive drugs had a baseline biochemical test and from 20% to 79% had any follow-up monitoring. In only 7 of the 12 studies that examined follow-up monitoring did more than half of the patients have any monitoring. Overall, this systematic review provides evidence that monitoring as recommended by published guidelines is not commonly undertaken. Only two studies were identified that examined patients with both baseline testing and follow-up monitoring. Omission of one or the other limits the ability to analyse the effect of treatment on electrolyte concentrations or renal function. There is limited research on the patient factors associated with monitoring and further work is required to determine the impact of monitoring on adverse patient outcomes. Important barriers to effective monitoring exist and this review emphasizes that these have not yet been overcome.     

Cost-effectiveness of therapeutic drug monitoring: a systematic review

There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked interpatient pharmacokinetic variability. Individualized therapy with such drugs requires therapeutic drug monitoring (TDM) to obtain the desired clinical effects safely. Cost-effectiveness analysis in health care is still at an early stage of development, especially for TDM. A systematic review was carried out to document studies that have addressed the cost-effectiveness of TDM. The Cochrane database and Medline were searched. References identified by this approach were then searched manually for relevant articles. Very few studies have been performed that document the cost-effectiveness of TDM, and TDM has been demonstrated to be cost-effective only for aminoglycosides. For the other classes of drugs that are monitored, the rationale for TDM has been supported, but appropriate cost-effectiveness analyses have not been performed. Because the use of many of these drugs without TDM would increase the risk of under- or overdosing, emphasis should not be placed solely on cost-effectiveness but rather on how such interventions can be applied in the most cost-effective and clinically useful manner.     

A phased approach to drug development

Summary It is possible in the UK to carry out a phased approach to drug development that is designed to assist in the selection of a candidate drug for development from a series of compounds; minimize the amount of animal work (toxicological and metabolic) necessary to permit early evaluation in man; introduce a more rational basis for decision making by setting criteria that must be satisfied before entry can be made into the next phase of development; obtain safety, pharmacokinetic, and possibly dynamic data in man within about 16 months of receipt of the compound.SeeJ. Pharmacokin. Biopharm. 17:521–523.     

A phased approach to drug development

It is possible in the UK to carry out a phased approach to drug development that is designed to assist in the selection of a candidate drug for development from a series of compounds; minimize the amount of animal work (toxicological and metabolic) necessary to permit early evaluation in man; introduce a more rational basis for decision making by setting criteria that must be satisfied before entry can be made into the next phase of development; obtain safety, pharmacokinetic, and possibly dynamic data in man within about 16 months of receipt of the compound.     

Thyroid replacement therapy: a rational approach to laboratory monitoring

A brief summary of the diagnostic laboratory criteria for primary hypothyroidism and the practical aspects of the pharmacology of thyroid hormone therapy are presented. A minimal testing protocol for the adequacy of replacement therapy is advocated based on classic studies of restored thyroid function.     

万古霉素治疗药物监测研究进展

万古霉素是治疗耐甲氧西林金黄色葡萄球菌的首选药,但在使用万古霉素的过程中,血药浓度过低会导致治疗效果不佳、过高会出现耳和肾毒性,且体内代谢个体差异大,易受患者的年龄、体质量、肝肾功能、基础疾病状态、给药间隔时间和重症感染等多种因素的影响。因此为了保证治疗有效性和安全性,临床常采取血药浓度监测来指导万古霉素个体化用药。从万古霉素血药浓度监测与疗效和不良反应的相关性,目前常用的药物监测方法（包括高效液相色谱、超高效液相色谱串联质谱法、免疫分析法等）,不同人群万古霉素血药浓度的影响因素等方面进行了归纳总结,以期为该药的临床合理应用提供指导。     

A systematic approach to investigate the impact of nonclinical blood processing deviations on large-molecule drug bioanalysis

During nonclinical regulated toxicology studies, blood processing protocol deviations may negatively impact sample integrity and bioanalytical results. Standard practices for resolution of blood processing issues are not well established across the industry. In this article, using an illustrative example, we present a systematic approach to investigate and assess the impact of nonclinical blood processing protocol deviations that involve: assessment of the potential impact of deviations on toxicokinetic evaluation, performance of additional blood processing stability tests to ensure study sample integrity and establishment of study sample results reporting procedures to meet both scientific and regulatory quality requirements. This thorough and systematic approach can serve as a model for other analogous situations.     

Multivariate chemometric approach to thermal solid-state FT-IR monitoring of pharmaceutical drug compound

The study of thermal-related solid-state reaction monitored by spectroscopic method needs the use of advanced multivariate chemometric approach. It is because visual inspection of spectral data on particular functional groups or spectral bands is difficult to reveal the complete physical and chemical information. The spectral contributions from various species involved in the solid-state changes are generally highly overlapping and the spectral differences between reactant and product are usually quite minute. In this article, we demonstrate the use of multivariate chemometric approach to resolve the in situ thermal-dependent Fourier-transform infrared (FT-IR) mixture spectra of lisinopril dihydrate when it was heated from 24 to 170 degrees C. The collected FT-IR mixture spectra were first subjected to singular value decomposition (SVD) to obtain the right singular vectors. The right singular vectors were rotated into a set of pure component spectral estimates based on entropy minimization and spectral dissimilarity objective functions. The resulting pure component spectral estimates were then further refined using alternating least squares (ALS). In current study, four pure component spectra, that is, lisinopril dihydrate, monohydrate, anhydrate, and diketopiperazine (DKP) were all resolved and the relative thermal-dependent contributions of each component were also obtained. These relative contributions revealed the critical temperature for each transformation and degradation. This novel approach provides better interpretation of the pathway of dehydration and intramolecular cyclization of lisinopril dihydrate in the solid state. In addition, it can be used to complement the information obtained from differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).     

A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting risperidone

Introduction: This systematic review of therapeutic drug monitoring (TDM) identifies three long-acting injectable (LAI) risperidone formulations.

Areas covered: Limited data is available on two formulations (RBP-7000 and in Situ Microparticle), but 20 TDM articles on the microsphere formulation were found. Risperidone TDM includes the serum concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, used for calculating: 1) the risperidone/9-hydroxyrisperidone (R/9-OH-R) ratio (a measure of CYP2D6; values >1 are indicative of a CYP2D6 poor metabolizer) and 2) the total risperidone concentration-to-dose (C/D) ratio (a measure of risperidone clearance with a normal value around 7 in oral risperidone). The weighted mean R/9-OH-R ratio was 0.48 (approximately twice that of oral risperidone TDM) in a combined analysis from 329 patients in 6 risperidone LAI studies without major confounders. The total C/D ratios from 297 patients in 6 risperidone LAI studies ranged from 7.4 to 9.7 ng/ml/mg/day with a weighted mean of 8.8 ng/ml/mg/day.

Expert commentary: Clinicians using TDM for risperidone LAI microsphere formulation need to: 1) consider steady state to be reached ≥ 6 weeks after the first injection, 2) pay attention to a) co-medications with inducers/inhibitors, b) severe inflammations/infections, and c) hepatic/renal impairment, and 3) use Castberg’s recommendation to calculate risperidone dosing.     

A systematic review and combined analysis of therapeutic drug monitoring studies for oral paliperidone

Introduction: This article includes a combined analysis of therapeutic drug monitoring (TDM) studies and a review of the marketer’s data on pharmacological mechanisms.

Areas covered: An article search led to the inclusion of 21 paliperidone studies in the systematic review plus 2 case reports. Paliperidone clearance was calculated from: 1) steady-state studies using concentration/dose (C/D) ratios, and 2) single-dose studies describing 24-h area under the curve calculations. The marketed extended-release formulation has 28% bioavailability. Calculated mean C/D ratios (ng/ml/mg/d) were: 1) 4.09 in 6 studies of 221 non-Korean and non-geriatric adult patients, 2) 2.59 in 2 studies of 100 Korean adult patients, and 3) 6.89 in 1 study with 15 elderly Japanese patients. The limited drug–drug interaction studies indicated that carbamazepine is a clinically relevant inducer requiring three times the dosage, and that valproate, probably an inhibitor, requires half the dosage. Renal impairment markedly decreased paliperidone elimination, and other antipsychotics should be considered.

Expert Commentary: We recommend more use of: 1) paliperidone TDM in clinical practice, 2) TDM when moving from oral to long-acting paliperidone, 3) better designs for paliperidone TDM studies, 4) laboratory studies on paliperidone pharmacokinetic mechanisms, and 5) TDM studies comparing paliperidone and risperidone dosing.     

A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting paliperidone

ABSTRACT

Introduction: This is a combined analysis of therapeutic drug monitoring (TDM) studies of long-acting injectable paliperidone formulations: monthly (PP1M) and three-month (PP3M) injections.

Areas covered: Fourteen PP1M articles and one PP3M article were identified. Using the paliperidone concentration/dose (C/D) ratio as a measure of clearance provided a weighted mean of 7.7 ng/ml per mg/day among 69 patients from three steady-state PP1M studies (twice as high as oral paliperidone). C/D ratios were: 1) higher by a factor of 1.26 in 12 geriatric patients, 2) lower in obese patients, and 3) 50% lower in three patients taking carbamazepine. No clinically meaningful PP3M pharmacokinetic data have been published.

Expert commentary: Half-life studies and more TDM PP1M studies using steady state are urgently needed. Early TDM studies may help orient PP1M dosing but steady state may not be reached until after the ninth injection (8 months). PP3M may take > 1 year to reach steady state. Any clinician considering switching patients to PP1M: 1) should switch from oral risperidone to PP1M rather than from oral paliperidone to PP1M, and 2) become proficient in paliperidone TDM to use during switches. TDM is highly recommended for patients with abnormal clearance (from obesity, geriatric age, or potent inducers).     

Practical approach to the use and monitoring of dofetilide therapy.

FDA's requirements for the use of dofetilide are described, and one hospital's strategy for meeting the requirements is discussed. Dofetilide is a specific class III antiarrhythmic agent approved for use in the conversion of atrial fibrillation and atrial flutter and the maintenance of normal sinus rhythm. It is available as an option for highly symptomatic patients who fail to respond to or do not tolerate other antiarrhythmic agents and patients with structural heart disease. Because of the risk of torsade de pointes associated with dofetilide, FDA has mandated in-hospital initiation of dofetilide therapy and has restricted its availability to hospitals and prescribers who have received appropriate education on dofetilide treatment initiation and dosing. Control of the drug's distribution is limited to a single wholesaler and a single mail-order pharmacy. These restrictions, along with the FDA labeling and the inherent risks associated with dofetilide use, have made this drug a complicated agent to use within an institution. When dofetilide was added to the formulary at Harper University Hospital, policies and procedures were developed to ensure appropriate use and monitoring. The use of dofetilide within health systems requires detailed procedures for prescribing, dispensing, and monitoring and thorough education of caregivers about those procedures. Pharmacists have a pivotal role in ensuring the appropriate use of dofetilide.