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Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 9/2013 (693-703)

Pharmacokinetics of vildagliptin in patients with varying degrees of renal impairment

Yan-Ling He¹, Kenneth Kulmatycki¹, Yiming Zhang², Wei Zhou², Christine Reynolds², Monica Ligueros-Saylan² and Ann Taylor¹

¹Novartis Institutes for BioMedical Research, Cambridge, MA, and ²Novartis Pharmaceuticals, East Hanover, NJ, USA
Objective: The kidney plays a key role in both the metabolism and excretion of vildagliptin. This study was designed to investigate the effects of varying degrees of renal impairment (RI) on the pharmacokinetics of vildagliptin. Methods: A total of 96 subjects were enrolled, and each subject received vildagliptin 50 mg dosed orally once daily for 14 days. Vildagliptin and metabolite concentrations in plasma and urine were measured on Days 1 and 14. Results: Compared to age-, gender-, BMI-matched subjects with normal renal function, the mean AUC of vildagliptin after 14 days in patients with mild, moderate, and severe RI increased by 40%, 71%, and 100%, respectively, and the C_max of vildagliptin showed similar and minimal increases of 37%, 32% and 36%, respectively. Conclusions: These pharmacokinetics results suggest that 50 mg once daily is an appropriate dose and recommended for patients with moderate and severe renal impairment.Correspondence to:
Yan-Ling He, PhD, DMSci
Translational Medicine
Novartis Institutes for BioMedical Research, Inc.
220 Massachusetts Avenue
Cambridge, MA 02139, USA
Email: [email protected]

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 12/2013 (948-957)

High-quality triplicate electrocardiogram monitoring in a first-in-man study: potential for early detection of drug-induced QT prolongation

Yan-Ling He¹, Yiming Zhang², Jing-He Yan², Wei Zhou², Steven Komjathy³ and Ann Taylor¹

¹Novartis Institutes for BioMedical Research, Cambridge, MA, ²Novartis, East Hanover, NJ, and ³Charles River Clinical Services Northwest Inc., Tacoma, WA, USA
Background: QT interval prolongation is associated with an increased risk of potentially fatal ventricular tachycardias, including torsade de pointes. Regulatory guidance recommends the “thorough QT/QTc” (TQT) study as the gold standard for assessing the propensity of novel nonantiarrhythmic drugs to delay cardiac repolarization. An opportunity exists, however, to use high-quality electrocardiogram (ECG) data from first-in-man trials as an exploratory and complementary approach to gain early insight into potential risk of QT prolongation. Methods: We collected high-quality, triplicate, 12-lead ECG data during a first-in-man trial of a drug developed for the treatment of Type 2 diabetes that had shown in vitro hERG inhibition and potential to prolong QT intervals in an animal model. Results: QTc prolongation was observed at the highest dose, leading to a maximum QTcF prolongation > 19 ms at 6 hours after the 14th daily dose. QTcF increases from time-matched baseline relative to placebo were positively correlated with peak plasma concentrations. Conclusions: Clinically relevant QT interval prolongations can be detected during first-in-man studies using high-quality ECG monitoring. Such data may facilitate early decision making on whether to terminate the development of a compound and invest resources in more promising molecules; and it may enable more efficient TQT study design or preclude the need for future TQT studies.Correspondence to:
Yan-Ling He, PhD, DMSc
Translational Medicine
Novartis Institutes for BioMedical Research
220 Massachusetts Avenue, Building 605
Cambridge, MA, 02139-3584, USA
Email: [email protected]

Abstract

Trace Elements and Electrolytes, Vol. 42 – No. 2/3 /2025 (60-66)

Lithium poisoning misdiagnosed as hyperthyroid crisis in a patient with hyperthyroidism: A case report with review of literature 

Zichen Rao, Chunyan Zhu, and Yiming Zhang

Department of Endocrinology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, Zhejiang, China
Introduction: The role of lithium (Li) in the treatment of Graves’ disease (GD) remains a contentious issue. A literature review revealed no reports of lithium poisoning in patients with hyperthyroidism treated with lithium. Here we present a case of hyperthyroidism in a patient who developed lithium poisoning after lithium treatment and was initially misdiagnosed as hyperthyroid crisis.
Case report: A 31-year-old female patient with hyperthyroidism presented with dyspnea, chest tightness, abdominal swelling, and diarrhea for 3 consecutive days. Physical examination revealed typical features associated with hyperthyroidism. Further laboratory investigations confirmed a hyperthyroid state with decreased thyroid stimulating hormone levels, significantly increased free thyroxine levels, and high levels of thyroid receptor antibodies. Additional diagnostic tests revealed pulmonary edema and compromised left ventricular function. Initially, the patient was treated with methimazole; however, she experienced agranulocytosis, which necessitated switching to lithium carbonate. After 18 days of lithium carbonate treatment, the patient again developed chest tightness, dyspnea, edema, accompanied by lethargy, confusion, visual hallucination, and other symptoms, and was diagnosed with hyperthyroidism crisis. However, subsequent lithium concentration monitoring revealed elevated serum lithium levels (2.82 mmol/L), indicating lithium poisoning. When lithium was stopped, the symptoms disappeared quickly. After this episode, the patient received final treatment with iodine-131 to effectively control hyperthyroidism.
Conclusions: Our case highlights the potential lithium toxicity of low doses of lithium carbonate in the treatment of hyperthyroidism, especially in patients with an imminent hyperthyroidism crisis. Close monitoring of serum lithium levels is essential for patients receiving lithium therapy for hyperthyroidism. Correspondence to:
Yiming Zhang, MD
Department of Endocrinology
The Quzhou Affiliated Hospital of Wenzhou Medical University
Quzhou People’s Hospital
Quzhou, 324000, Zhejiang, China
Email: [email protected]

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