Many outpatients taking drugs with a narrow therapeutic range do not receive drug concentration monitoring to prevent toxicity

Lithium is commonly prescribed for mood stabilization in bipolar disorder. Lithium has a narrow therapeutic range (0.8−1.2 mmol/L), and even chronic users may unexpectedly develop toxic levels. Toxicities manifest in various ways. The authors report the case of a patient who developed sinus bradycardia and asystolic arrest with an elevated serum lithium level.

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Relevant Issues of Planning Bioequivalence Studies of Drugs with a Narrow Therapeutic Range

The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products ◽

10.30895/1991-2919-2020-10-3-201-210 ◽

2020 ◽

Vol 10 (3) ◽

pp. 201-210

Author(s):

D. P. Romodanovsky

Keyword(s):

Valproic Acid ◽

Therapeutic Range ◽

Individual Variation ◽

Generic Drugs ◽

Statistical Processing ◽

Bioequivalence Study ◽

Pharmacokinetic Studies ◽

Study Planning ◽

Narrow Therapeutic Range ◽

Microsoft Office

In order to be registered, generic drugs with a narrow therapeutic range have to undergo bioequivalence or therapeutic equivalence studies. In most cases, comparative pharmacokinetic studies and demonstration of bioequivalence between the test and the reference products are sufficient for this group of drugs. However, there is no established official definition in Russia for the group of drugs that are regarded as having a narrow therapeutic range. Evaluation of bioequivalence of such drugs has to be performed providing for narrower confidence intervals, which entails certain problems at the stage of bioequivalence study planning. Finding solutions to the problems stated above is of great importance. The aim of the study was to develop approaches to planning bioequivalence studies of drugs with a narrow therapeutic range. Materials and methods: the paper analyses the results of 33 bioequivalence studies of drugs with a narrow therapeutic range, in which Cmax, AUC0-t, and tmax were calculated. Intra-individual variation and weighted mean intra-individual variation of Cmax and AUC0-t were estimated in the study. Statistical processing was performed using IBM SSPS Statistics v.25. and Microsoft Office Excel 2016. Results: the paper summarises criteria for categorising drugs as having a narrow therapeutic range and describes general requirements for assessing their bioequivalence. A number of bioequivalence studies of generic valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine products which meet the criteria for drugs with a narrow therapeutic range, were analysed retrospectively. The data on their pharmacokinetics and intra-individual variation were calculated. It also summarises requirements for bioequivalence evaluation of drugs with a narrow therapeutic range. The paper gives product-specific recommendations for performing bioequivalence studies. Conclusion: the study helped to formulate approaches to the planning of bioequivalence studies of generic drugs with a narrow therapeutic range using the examples of valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine.

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Neoral: A Microemulsion Cyclosporine

Journal of Transplant Coordination ◽

10.1177/090591999600600103 ◽

1996 ◽

Vol 6 (1) ◽

pp. 5-8 ◽

Cited By ~ 1

Author(s):

David I Min

Keyword(s):

Therapeutic Range ◽

Survival Rates ◽

Drug Level ◽

Oral Solution ◽

Transplant Recipients ◽

Microemulsion Formulation ◽

Narrow Therapeutic Range ◽

Patient And Graft Survival ◽

Clinical Stability

Cyclosporine (Sandimmune), introduced in the 1980s, improved patient and graft survival rates primarily by decreasing the frequency and severity of early, acute rejection. Today, the challenge for coordinators and clinicians is to promote long-term clinical stability in transplant recipients. This requires maintaining the cyclosporine blood level within a relatively narrow therapeutic range to ensure adequate and stable immunosuppression, thus reducing the risk of rejection caused by a suboptimal drug level or drug-related toxicity because of a level above the therapeutic range. However, the clinical use of Sandimmune is complicated by low bioavailability and highly variable pharmacokinetics that provide management challenges and can affect clinical outcomes adversely. Neoral, a new oral microemulsion formulation (in capsules and oral solution) of cyclosporine, improves the bioavailability and pharmacokinetics of cyclosporine and reduces inter- and intraindividual pharmacokinetic variability with a safety profile comparable to that of Sandimmune.

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