A lower concentration of a prodrug does not necessarily mean less exposure to its active product. A historical 2016 crossover study of lisdexamfetamine provides a direct example: the prodrug and d-amphetamine gave different bioequivalence results after capsule contents were mixed with orange juice or yogurt.
What administration conditions were compared?
Thirty healthy adults entered an open-label, randomized, three-period crossover study. Each treatment used a 70-mg lisdexamfetamine dimesylate capsule: swallowed intact with water, or with its contents mixed into four ounces of orange juice or yogurt. Treatment periods had seven-day washouts, and serial blood sampling extended to 96 hours.
Participants followed controlled fasting and ingestion schedules. All 30 entered the pharmacokinetic analysis set; one withdrew after dosing in the third period. The study did not administer 70 mg of d-amphetamine: the stated dose was the prodrug salt.
What did active d-amphetamine show?
The prespecified criterion required the 90% confidence interval for a geometric mean ratio to fall within 0.80–1.25. Peak d-amphetamine concentration and both exposure-area measures met that criterion for orange juice and yogurt relative to the intact capsule.
For example, the d-amphetamine exposure-area ratio extrapolated to infinity was 0.986 with orange juice, 90% interval 0.955–1.019, and 0.945 with yogurt, interval 0.915–0.976. Those are relative pharmacokinetic estimates, not concentrations in ng/mL or percentages of a clinical response.
What did the intact prodrug show?
Lisdexamfetamine itself gave a different result. With orange juice, its peak-concentration ratio was 0.641, 90% interval 0.582–0.707, and its extrapolated exposure-area ratio was 0.716, interval 0.647–0.792. Both intervals fell below the acceptance range. With yogurt, the prodrug peak interval also extended below the lower boundary.
Relabeling these prodrug findings as reduced active-amphetamine exposure would reverse the study’s central distinction. The identity of the measured compound is therefore essential, even when both results come from the same blood draw and administration.
Does bioequivalence mean identical curves?
No. It means the specified intervals satisfied the study’s predefined comparison rule for the tested endpoints. The yogurt d-amphetamine exposure estimate illustrates the point: its interval was below a ratio of 1 but remained inside the accepted range. Numerical difference and failure of a bioequivalence criterion are different statements.
These are group comparisons under controlled conditions. They do not guarantee identical concentrations at every time point for every individual, and the 90% interval is not an individual’s prediction interval.
What limits the practical interpretation?
The experiment involved healthy adults, a single dose and two specific mixing vehicles. The authors identified uncertainty about lower doses and other foods or liquids. It was not a trial comparing symptom control, driving ability or long-term safety across administration methods.
Reported adverse events were mild, but the small single-dose sample cannot establish the absence of uncommon or delayed harms. Nor does the experiment support attributing an unusual individual concentration solely to what the capsule was mixed with.
What should be preserved in a toxicology account?
Identify the administered salt, the measured analyte, the specimen, the endpoint and the comparison rule. This study supports a constrained pharmacokinetic conclusion about active d-amphetamine under its tested conditions. It does not supply a dosing instruction or a rule for converting prodrug concentrations into impairment.
Source
Ermer J, Corcoran M, Lasseter K, Martin PT. Study of lisdexamfetamine and d-amphetamine relative bioavailability after mixing capsule contents with food or drink. Therapeutic Drug Monitoring. 2016;38(6):769–776. DOI: 10.1097/FTD.0000000000000343. Full article with complete title; bibliographic record.