A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate.
OBJECTIVE
NN703 (tabimorelin) is an orally active growth hormone (GH) secretagogue intended for use as an alternative to daily injections of GH. In vitro studies in human liver microsomes have indicated that NN703 is a mechanism-based inhibitor of CYP3A4. The aim of the present study was to investigate in man the effects of NN703 on the pharmacokinetics of midazolam, a substrate of CYP3A4.


METHODS
Seventeen adult male subjects were enrolled in the study, and each received an oral dose of midazolam (7.5 mg) on four occasions: at baseline (day 1), after one dose of NN703 (day 3), after 7 days once daily NN703 treatment (day 9) and after a 7-day washout period (day 16). The pharmacokinetics of midazolam and its main metabolite, alpha-hydroxymidazolam, were investigated.


RESULTS
Following a single dose of NN703 (day 3), the AUC of both midazolam and alpha-hydroxymidazolam increased by 64% and 34%, respectively (P=0.0001 for both). After repeated NN703 dosing (day 9), NN703 levels reached steady state, and midazolam AUC further increased to 93% relative to baseline (P=0.0001), whereas alpha-hydroxymidazolam AUC decreased slightly and was 11% higher than baseline (n.s.). Following the washout period (day 16), midazolam AUC decreased to values lower than those on day 3 and day 9, but still significantly (45%) higher than baseline levels (P=0.0001). The C(max) values of midazolam and alpha-hydroxymidazolam demonstrated a pattern similar to the AUC, but the effect following repeated NN703 dosing was more pronounced. The t(1/2) of midazolam increased from day 1 to day 3 (P=0.0483) but was essentially unchanged at steady state on day 9.


CONCLUSIONS
This study shows that administration of NN703 and midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.
Zdravkovic
Milan
M
Novo Nordisk A/S, Research and Development, Denmark. mzd@novonordisk.com
Olsen
Anette K
AK
Christiansen
Tina
T
Schulz
Rainer
R
Taub
Mitchell E
ME
Thomsen
Mikael S
MS
Rasmussen
Michael H
MH
Ilondo
Mapoko M
MM
D000759:Adjuvants, Anesthesia / Q000378:metabolism / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004151:Dipeptides / Q000009:adverse effects / Q000494:pharmacology*; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D008875:Middle Aged; D013997:Time Factors
D000759:Adjuvants, Anesthesia; D065607:Cytochrome P-450 Enzyme Inhibitors; D004151:Dipeptides; D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C120631:tabimorelin; D008874:Midazolam