Clinical Pharmacology · MU Sofia

9. Clinical Drug Trials - Phase 1: Design, target population, aims.

Covers Phase I trials as the first use of a new drug in humans, with safety as the overriding principle. It sets out who is enrolled, usually healthy volunteers and sometimes patients for toxic drugs, and the aims: tolerability, pharmacokinetics, early pharmacodynamics and finding the maximum tolerated dose. Design features include how the starting dose is derived from animal data, the 3 + 3 escalation scheme with its toxicity threshold, and the TGN1412 case.

Inside: 4 sections · 15 flashcards · 2 min

Topic 9 of 30 in the MU Sofia syllabus for Clinical Pharmacology (Medicine, Year 5). The free AceMed note covers it in 4 sections, about 331 words (2 min of reading), with 15 flashcards.

In this note

  1. Introduction
  2. Target population
  3. Aims
  4. Design

Introduction

Phase I is the first use of a new drug in humans ("first-in-human", human pharmacology). Its overriding principle: safety comes before everything else.

Target population

  • Usually healthy volunteers, about 20–80 (often 12–50 per study), mostly young men, in specialised units with close monitoring.
  • Patients instead of volunteers when the drug is too toxic for healthy people: anticancer drugs, some HIV and biological treatments.

Aims

  1. Tolerability and safety with single and then multiple ascending doses.
  2. Pharmacokinetics: absorption, distribution, metabolism, excretion, half-life, food effects, dose proportionality.
  3. Early pharmacodynamics and target engagement (biomarkers).
  4. Find the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), and so the dose range for phase II.

Design

Starting dose

  • A fraction of the dose that was safe in animals: about 1/10 of the NOAEL-derived human equivalent dose (1/50–1/100 of the NOAEL in the most sensitive species), or, for high-risk biologicals, 1/10 of the MABEL (minimal anticipated biological effect level).
  • Anticancer drugs: 1/10 of the dose lethal to 10% of rodents (LD₁₀), or 1/3 of the lowest toxic dose in larger animals.

Dose escalation

  • Single ascending dose (SAD), then multiple ascending dose (MAD) cohorts; sentinel dosing (one subject first) for new mechanisms.
  • 3 + 3 design: 3 patients per dose level; if 1 of 3 has a DLT, add 3 more; if ≥ 2 of 6 have DLT, the dose is too high. The MTD is the level below it (a DLT rate of ≤ 1 in 6, about 33% threshold).
  • Modified Fibonacci steps: dose increments of 100%, 67%, 50%, 40%, then 25–33%.
  • Placebo-controlled, often single-blind within cohorts; frequent clinical, ECG and laboratory checks.

Three goals for the recommended phase II dose

Reached safely (few serious toxicities), efficiently (few subjects) and reliably (statistical confidence).

Lesson of TGN1412 (2006): six volunteers developed cytokine storm after a dose based on animal NOAEL; this led to the MABEL approach and staggered dosing.

Phase I asks "is it safe, and how does the body handle it?", usually in a few dozen healthy volunteers, except for cytotoxic drugs.

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