Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

LITHIUM

Summary of PDE for Lithium

Lithium (Li)

Oral

Parenteral

Inhalation

PDE (µg/day)

560

280

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Introduction

Lithium (Li) is a common metal that is present in plant and animal tissues. Lithium is being used alone or in combination with other metals as catalyst. Lithium compounds (e.g., lithium aluminum hydride) are being used as reagents in organic synthesis. Lithium exists commonly as a salt in the +1 oxidation state only.

Safety Limiting Toxicity

Lithium is used as a human therapeutic, and extensive human data exists in the administration of lithium salts in the treatment of mania, bipolar disorder, and recurrent unipolar depression. Treatment with lithium salts requires frequent controls by the treating physician, including measurement of lithium concentrations. The therapeutic range for lithium has been established at 0.6-1 mmol/L in serum, depending upon the formulation administered (Grandjean and Aubry, 2009). The therapeutic margin is narrow and Li toxicity can occur at therapeutic exposures. Lithium treatment in humans is mainly associated with an increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain (McKnight et al , 2012). The usual recommended dose is 300-600 mg three to four times a day (US FDA, 2011). The data was reviewed to identify the safety limiting toxicities based on routes of administration.

PDE – Oral Exposure

Human experience with lithium was used as the point of departure for this PDE. When using the lowest human single oral dose of 300 mg lithium carbonate (56 mg Li), the oral PDE is calculated as follows:

PDE = 56 mg/d / 1 x 10 x 1 x 1 x 10 = 0.56 mg/d = 560 µg/day

A factor of 10 was chosen for F5 because a LOAEL (one-third the recommended daily dose) was used to set the PDE.

PDE – Parenteral Exposure

There are no adequate data to develop a parenteral PDE. However, based on oral bioavailability of 85% (Grandjean and Aubry, 2009), the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 2 (as described in Section 3.1).

PDE = 560 µg/d / 2 = 280 µ/day

PDE – Inhalation Exposure

Rabbits were exposed to lithium chloride at 0.6 and1.9 mg/m 3 for 4-8 weeks, 5 days/week for 6 hours/d (Johansson et al. 1988). Lungs were studied by light and electron microscopy with focus on inflammatory changes. No significant effects were reported, so the highest dose was used to set the PDE. Taking into account the modifying factors (F1- F5 as discussed in Appendix 1), the inhalation PDE is calculated as:

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