Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant.
OBJECTIVE
To determine the pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc.).


METHODS
Thirty-four male monkeys (Macaca fascicularis) received bilateral 0.7-mg DEX implants. Blood, vitreous humor, and retina samples were collected at predetermined intervals up to 270 days after administration. DEX was quantified by liquid chromatography-tandem mass spectrometry, and cytochrome P450 3A8 (CYP3A8) gene expression was analyzed by real-time reverse transcription-polymerase chain reaction.


RESULTS
DEX was detected in the retina and vitreous humor for 6 months, with peak concentrations during the first 2 months. After 6 months, DEX was below the limit of quantitation. The C(max) (T(max)) and AUC for the retina were 1110 ng/g (day 60) and 47,200 ng · d/g, and for the vitreous humor were 213 ng/mL (day 60) and 11,300 ng · d/mL, respectively. The C(max) (T(max)) of DEX in plasma was 1.11 ng/mL (day 60). Compared with the level in the control eyes (no DEX implant), CYP3A8 expression in the retina was upregulated threefold up to 6 months after injection of the implant (0.969 ± 0.0565 vs. 3.07 ± 0.438; P < 0.05 up to 2-month samples).


CONCLUSIONS
The in vivo release profile of the DEX implant in an animal eye was similar to the pharmacokinetics achieved with pulse administration of corticosteroids (high initial drug concentration, followed by a prolonged period of low concentration). These results are consistent with those in clinical studies supporting the use of the DEX implant for the extended management of posterior segment diseases.
Chang-Lin
Joan-En
JE
Department of Research and Development, Allergan, Inc., Irvine, CA, USA. lin_joan-en@allergan.com
Attar
Mayssa
M
Acheampong
Andrew A
AA
Robinson
Michael R
MR
Whitcup
Scott M
SM
Kuppermann
Baruch D
BD
Welty
Devin
D
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003692:Delayed-Action Preparations; D003907:Dexamethasone / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004343:Drug Implants; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005938:Glucocorticoids / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006207:Half-Life; D008252:Macaca fascicularis; D008297:Male; D012160:Retina / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D014822:Vitreous Body / Q000378:metabolism*
D003692:Delayed-Action Preparations; D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A