Following criticisms of data presented by Abbott researchers at last week's Fifth International Congress on Drug Therapy in HIV Infection, Dale Kempf, a senior researcher at Abbott, has contacted aidsmap to respond to two criticisms expressed by Dr. Andrew Hill, International Medical Manager for Fortovase at Roche.
The first issue is the suggestion that data from a study in PI-experienced patients (study M98-957) shows a median IQ (ratio of trough drug concentration to minimum concentration needed to inhibit viral replication by 50%) of 9.9, vastly lower than the IQ stated for wild-type HIV (>75, according to Abbott data), and suggestive of the probability that well characterised reductions in susceptibility to other PIs may also cause much greater reductions in susceptibility to ABT-378/r than hitherto expected.
Dale Kempf rejects that suggestion.
"The median IQ of 9.9 in the study presented by Dr. Hsu is to be expected given that to enroll in that study, patients had to have already failed at least two PIs (the median number of prior PIs was 3)" he told aidsmap.
"The range of susceptibility to ABT-378 at baseline was from 0.5 to 96-fold. Since the IC50 is by definition part of the IQ, a highly experienced population will certainly have a much lower IQ than a treatment-naive population. So the median of 9.9 in that study is consistent with the calculated IQ for naïve patients that we have reported."
The second issue concerns inter-patient variations in plasma levels of ABT-378/r. Andrew Hill highlighted findings included in the US data sheet of ABT-378/r, which suggest a huge variation between individuals in the plasma levels of ABT-378/r. Mean trough concentrations of ABT-378/r were found to lie within the range of 1.5 ug/mL to 9.5 ug/mL(the 95% confidence intervals), with a mean of 5.5 ug/mL.
"The crux of Dr. Hill's argument, I assume, rests on his assumption that the distribution of single values around the mean is a normal one (in other words, shaped like a bell curve)" said Dale Kempf.
"If a distribution of points around a mean or average is normal, then 95% of the points will lie within 2 standard deviations of the mean in either direction. Using the standard deviation above (4.0), Dr. Hill concludes that a significant percentage of subjects would be receiving very low levels of ABT-378, because 5.5 minus 2 times 4.0 is less than zero. The error in that conclusion, however, is the assumption that the data is normally distributed (i.e. shaped like a bell curve). In fact, the distribution is not normal, and the lowest Ctrough that has been measured in treatment-naive patients (n=21) is 0.6 micrograms/mL, which produces a calculated IQ of 8".
"So the assertion that a significant number of patients receive very low Kaletra blood levels because of high variability is incorrect because of an incorrect assumption. In addition, the value in the package insert was based on studies where Kaletra was dosed without regard to food intake. We now know that dosing with food increases the Ctrough of ABT-378 as well as reduces variability, and this data has been submitted for presentation."
ABT-378/r is licensed in the United States under the trade name Kaletra but is not yet licensed in the European Union. The drug is available on a named patient basis in the UK.