Strategies for Transitioning from Intravenous to Oral Formulations in Phase 1 Trials

Introduction

Many drug development programs begin with intravenous (IV) formulations in Phase 1 to ensure controlled delivery and avoid bioavailability uncertainties. However, most commercial drugs aim for oral delivery due to patient convenience and lower costs. The transition from IV to oral forms—known as formulation bridging—requires careful planning, PK comparison, and regulatory strategy. This article explores how clinical teams bridge formulations effectively during early development, ensuring a smooth progression toward later-phase trials and eventual approval.

Why Start with IV Formulation?

Early IV administration offers several benefits:

• Complete bioavailability: 100% systemic exposure removes absorption variability
• Rapid onset and titratability: Ideal for PK modeling and acute tolerability data
• Supports absolute bioavailability studies: Used as a reference for oral dosing
• Formulation simplicity: Immediate readiness when oral preclinical data is insufficient

When and How to Bridge to Oral Formulations

Common Triggers for Bridging:

• Successful completion of initial SAD/MAD IV studies
• Emergence of promising oral formulations from CMC teams
• Positive modeling of oral bioavailability from preclinical species
• Regulatory alignment on Phase 2 oral dosing strategy

Typical Bridging Study Designs:

• Crossover Design: Healthy volunteers receive both IV and oral doses (randomized)
• Sequential Arms: IV SAD followed by oral SAD in separate cohorts
• Hybrid Designs: IV dose as microtracer alongside oral dose to estimate F%

Key Pharmacokinetic Parameters to Compare

1. Cmax (Peak Plasma Concentration)

• Oral Cmax typically lower and delayed due to absorption phase

2. AUC_0–∞ (Total Exposure)

• Used to calculate absolute bioavailability:
  F% = (AUC_oral/AUC_IV) x (Dose_IV/Dose_oral) x 100

3. Tmax (Time to Cmax)

• Important for correlating with PD/efficacy onset

4. CL and Vd (Clearance and Volume of Distribution)

• Derived from IV data; used to build PBPK models for oral dosing projections

Regulatory Expectations for IV-Oral Bridging

FDA Guidance

• Encourages early formulation bridging studies during Phase 1
• Accepts crossover or microtracer approaches for F% estimation
• Requires full characterization of PK and safety of the oral form prior to Phase 2

EMA View

• Focuses on consistency between formulations and comparability of systemic exposure
• Expects metabolite and food-effect data on oral formulation before later-phase use

CDSCO Consideration

• Allows Phase 1 bridging in India with protocol justification
• Requires bridging data to support any formulation change post-Phase 1

Operational Considerations During Bridging

1. Site Training and Formulation Handling

• Ensure blinding and preparation consistency
• Handle excipients, coating agents, or taste-masking with regulatory care

2. Safety Monitoring

• Compare tolerability between IV and oral doses
• Record changes in AEs, GI tolerance, and local reactions

3. Sample Timing Adjustments

• Oral samples require dense early-phase collection (0–6 hrs)
• IV samples focus on distribution and elimination

Modeling and Simulation to Support Bridging

1. Physiologically Based Pharmacokinetic (PBPK) Modeling

• Simulates oral absorption using IV data as baseline
• Incorporates solubility, permeability, pH dependency, and food effects

2. Population PK (PopPK) Modeling

• Combines data from both formulations to create a unified exposure model

3. Exposure-Response Integration

• Aligns PK curves with PD biomarkers or early efficacy signals

Examples of IV-Oral Bridging in Development

Case 1: Oncology Drug

• IV Phase 1 showed short half-life (~3 hrs); oral formulation achieved similar exposure
• F% calculated at 38%—Phase 2 advanced with oral capsule

Case 2: Anti-Infective Agent

• Oral tablets had reduced AUC vs IV; increased dose to match systemic exposure
• Food-effect study conducted before Phase 2

Case 3: CNS Molecule

• Oral formulation caused nausea; modified with enteric coating
• Bridging study repeated after reformulation

Common Challenges in IV to Oral Transition

• Low and variable oral bioavailability
• Excipient-related side effects or interactions
• Regulatory concern over formulation changes between phases
• Mismatch in exposure-response profile due to absorption kinetics

Best Practices for Bridging Formulations

• Design bridging studies early in the Phase 1 program
• Use sensitive and validated bioanalytical assays for low-dose detection
• Maintain detailed records of formulation properties, pH solubility, and stability
• Align clinical, regulatory, and CMC teams from the outset
• Use bridging study results to finalize dosing strategy for pivotal trials