To conduct a traditional absolute bioavailability study in humans a full safety toxicology package is required in order to administer the intravenous dose. Is the same required for Xceleron IVPK studies?
No. The intravenous dose in an IVPK study is kept very low, typically in the range of 1-10 ug. This dose is so low that the safety toxicology package used to support the oral dose can be used to justify the intravenous dose providing that there are also some exposure data. The draft ICH M3 guideline now includes the option for conducting microtracer intravenous doses (Section 7) without the full intravenous toxicology package. The worse case scenario is that a 14 day rat study may be required using the intravenous dose route based upon the guidelines covering microdosing (CPMP/SWP/2599, 23 June 2004 in the EU and the Exploratory IND January 2006 in the USA). If an unconventional dose vehicle is used, then a tolerance study may be required but this is relatively trivial.
If the intravenous dose is kept very low but the oral dose is administered at a therapeutically relevant level, how do you know that the plasma pharmacokinetics will be linear between the doses?
There are no issues of dose proportional pharmacokinetics in the IVPK study design. The drug concentration in plasma is determined overwhelmingly by the absorption of the extravascular dose (typically oral). The elimination pharmacokinetics of the intravenous dose are determined by the total drug concentration present in the plasma, which, as stated above, is driven by the oral dose. The technique was originally developed in the 1970’s using stable isotope tracers to eliminate potential dose dependent clearance effects that can occur when the intravenous and oral doses are given separately in a traditional absolute bioavailability study design. There were problems with the assay sensitivity using stable isotopes but this is eliminated using a rare isotope such as 14C and Accelerator Mass Spectrometry. The pharmacokinetics and values for absolute bioavailability are actually more reliable using the IVPK design than a traditional cross-over type study.
Compounds with very limited water solubility are very difficult to formulate for intravenous administration. How does IVPK help in this respect?
It is very unlikely that there will be any formulation problems using IVPK. A dose as low as 1ug (or even less) can be administered and so it is only necessary to dissolve this amount in the dosing solution, typically 50 mL. The effort involved in intravenous dose formulation is virtually eliminated.
With such low intravenous doses, how can you be sure that the method for measuring the drug concentration in plasma is sufficiently sensitive?
Accelerator Mass Spectrometry (AMS) is the most sensitive analytical method there is. If 200 nCi, 1ug of 14C-drug is administered, then the assay sensitivity will be around 1 fg/mL plasma.
Is it essential to use 14C-drug, can other isotopes be used as a tracer?
In theory yes but in practice there are difficulties. The isotope has to be rare so that background interference for naturally occurring isotope is minimized and this discounts virtually all stable isotopes. For example, the natural abundance of 13C is 1.1% and therefore to ensure the intravenous drug concentrations are sufficiently above background, relatively high levels of 13C-drug have to be administered. The relatively high intravenous dose then necessitates intravenous toxicology and formulation which defeats the object. 3H could be used but there are questions around tritium exchange and kinetic isotope effects. 14C is by far the most straightforward isotope to use. It has a natural abundance of just 10-10% and therefore the background does not adversely affect the sensitivity of the assay.
Does the administration of a radioisotope to humans raise any issues?
Not in the case of IVPK studies as the amount of radioactivity is so low. A typical amount of radioactivity used in a ABioPK study is 200 nCi, which is only about twice the naturally occurring background. There are some countries (eg Japan) where the administration of any amount of 14C is problematic but notwithstanding this, Xceleron has never experienced any significant regulatory issues in this respect.
I hear AMS analysis is more expensive than LC-MS, so is an IVPK study more expensive than a traditional absolute bioavailability study?
No, it is significantly less expensive. There is no need to conduct safety toxicology which will save typically $0.5 million plus the savings on intravenous dose formulation which can cost hundreds of thousands of dollars. In addition, it is possible to turn an IVPK around in about 4 months and with some drugs this is less time than it takes to develop an intravenous dose formulation.
What information is gained from an IVPK study, other than absolute bioavailability?
Because an intravenous dose is administered to human volunteers, an accurate measurement of the basic pharmacokinetic parameters of clearance and volume of distribution are obtained. In addition, if urine is collected and analyzed, renal clearance can be calculated.
Rather than saying the intravenous dose is given simultaneously with the oral dose, it is often stated that the intravenous dose is given concomitantly -what does this mean?
Depending upon the absorption characteristics of the oral dose, rather than give the intravenous dose at exactly the same time as the oral dose, the intravenous dose might be delayed until the tmax or given as an infusion over the same period as the drug is being absorbed. This is sometimes undertaken so that the clearance of the intravenous and oral drug are equivalent during the absorption phase but if the drug is absorbed relatively quickly, then this is probably unnecessary and the intravenous dose can be given along with the oral dose.
Enhanced Phase 1 Trials
Xceleron RSS Feed