Drug-Drug Interaction (DDI)

Interactions divide into two mechanisms that are often conflated. Pharmacokinetic interactions change how much drug reaches the site of action, through altered absorption, transporter activity, enzyme induction or inhibition, displacement from plasma protein binding, or competition for renal secretion. Pharmacodynamic interactions leave concentrations untouched and combine effects at the target or on a shared endpoint, additively or in opposition.

Therapeutic peptides mostly sidestep the classical cytochrome P450 story, because they are catabolised by peptidases into amino acids rather than metabolised by hepatic oxidation, so enzyme induction and inhibition tables largely do not apply. Their interactions are different in kind. GLP-1 receptor agonists slow gastric emptying, altering the rate and occasionally the extent of absorption of co-administered oral drugs, so labels advise care with oral agents of narrow therapeutic index. Adding an incretin to insulin or a sulfonylurea sharply raises hypoglycaemia risk, a pharmacodynamic interaction managed by reducing the background agent. Growth hormone alters cortisol and thyroid hormone handling and increases insulin resistance, which can render a previously adequate replacement dose inadequate.

Whether any of this matters depends on the therapeutic index of the affected drug. A modest exposure change is irrelevant for a drug with a wide window and consequential for warfarin, levothyroxine or an antiepileptic.

The recurring error is assuming that a peptide, being metabolised to amino acids, cannot interact with anything. The interactions that actually send people to hospital in this class are pharmacodynamic, and no metabolism argument protects against them. The second error is inferring safety from a silent label: unapproved compounds have no interaction studies at all.