Characterisation of the Human Carboxylesterase 1 (CES1) Mutation(s) Which May be Responsible for Markedly Reduced Conversion of Oseltamivir Phosphate to Oseltamivir Carboxylate

Oseltamivir is beneficial in the treatment of mild influenza. When given by mouth, oseltamivir phosphate (OP), the parent drug, is rapidly absorbed and rapidly converted to oseltamivir carboxylate (OC) by carboxylesterase enzymes (CES1) in the gut, plasma and liver. The mean time to maximum concentration of OP is 2 hours and OC is about 4. Plasma protein binding is ~42% for OP and <3% for OC. The latter has a volume of distribution at steady state after an IV dose of 23 to 26 L which is similar to extracellular water, consistent with its polar nature and low protein binding. OC and OP are renally excreted via glomerular filtration and active secretion via the organic anion transporter in the proximal renal tubules. In healthy subjects, oseltamivir carboxylate has a half life of 6-11 hours, achieves steady-state within 3 days (bd dosing) and has a higher AUC on Day 7 compared to Day 1.

Oseltamivir was associated with bizarre behaviour and acute confusion. Since these reports, similar events have also been associated with inhaled zanamivir, suggesting that the influenza rather than the drugs were responsible.

Because OP is more lipophilic than OC, it should cross the blood brain barrier more easily than OC. However, plasma to CSF ratios in 4 healthy volunteers were low for both substances, just over two and just under 3.5% for OP and OC, respectively. The low OP ratio is probably due to the actively export of OC from the brain by P-glycoprotein pump. In vitro and mice studies demonstrate that OP but not OC is a substrate for the glycoprotein P (P-gp) transporter and that the brain distribution of OC is affected by P-gp activity. PK simulations predict levels of OP that would be within the range of exposures observed in clinical studies without neuropsychiatric adverse effects.

One individual subject (individual X) from SEA004 "Long Term Influenza Prophylaxis with Inhaled Zanamivir or Oral Oseltamivir" had carboxylesterase 1 (CES1) gene mutation which may affect oseltamivir phosphate conversion. This means that the conversion of OP to OC in this subject can be substantially lower than the normal population.

This is a very important finding relevant both to antiviral efficacy and also potentially to toxicity because OP has no antiviral activity and may play a role in toxicity as a potentially neuroexcitatory compound. On the basis of in vitro data, the risk of cardiac toxicity should be not existent at therapeutic doses. OP had a variable effect on the hERG (human ether a go go K+ channel in cardiac muscle) but only at concentrations far in excess of those achieved with therapeutic doses; OC has no proarrhythmic effect.