Quantitative relationships between zidovudine exposure and efficacy and toxicity.

We examined the relationship between the concentrations of zidovudine in plasma given by continuous intravenous infusion to human immunodeficiency virus-positive pediatric patients and a surrogate marker of outcome (measured by the increase in the number of CD4-positive T cells) as well as drug-mediated toxicity (change in granulocyte count). The return of CD4-positive T cells was most strongly related to the number of these cells present at the start of therapy. Drug concentration data added little explanatory power to this relationship, indicating that the effect of zidovudine was near maximal throughout the range of concentrations examined. The change in granulocyte count was significantly correlated with zidovudine concentration both from weeks 1 through 8 and from weeks 8 through 12. These findings imply that it may be wise to stratify phase I antiretrovirus drug trials for the entry level of CD4-positive T cells if pharmacodynamic relationships with this marker as the dependent variable are to be sought. Continued efforts need to be made to derive quantitative relationships between drug exposure and measures of both efficacy and toxicity so that the maximal amount of information is derived from small phase I studies.

Population pharmacokinetics of zidovudine. The Veterans Administration Cooperative Studies Group.

The epidemic of human immunodeficiency virus infection has forced an unprecedented acceleration of drug development. The lack of effective therapy at present against many of the infectious complications of acquired immunodeficiency syndrome (AIDS) has forced the rapid clinical introduction of new agents. Population pharmacokinetic models are particularly attractive as a means of assessing drug disposition in cohorts different from those studied during necessarily abbreviated phase I trials. We have used the population pharmacokinetics model as implemented by the computer program NONMEM to study the distribution of zidovudine in a large number of patients who have AIDS-related complex and who are therefore at an earlier stage of immunosuppression than subjects in other studies. We confirm a clearance of drug identical to that seen by traditional methods but a larger volume of distribution than estimated previously in patients with AIDS. Possible reasons for this discrepancy and the use of this method in the development of antiretroviral therapy are discussed.

University professors' self-descriptions of left-right confusability: sex and handedness differences.

In a group of 364 university faculty members, frequency of self-reported confusion in left-right orientation was related to sex and handedness: among women, reports were statistically more common among left-handers than right-handers; among men, no relationship to handedness was evident. Over-all, women reported experiencing confusion more often than men did.