Effects of smoking cessation, acute re-exposure and nicotine replacement in smokers on AIR inhaled insulin pharmacokinetics and glucodynamics.
BACKGROUND
* Only one other study (Becker et al.) has reported on the influence of smoking cessation and smoking resumption on inhaled insulin pharmacokinetics and glucodynamics, concluding that the rapid changes associated with smoking resumption carry the risk for hypoglycaemia and thus should not be used by active smokers.


CONCLUSIONS
* This is the first euglycaemic clamp study on the impact of smoking cessation, acute smoking re-exposure and nicotine replacement on AIR((R)) inhaled insulin pharmacokinetics and glucodynamics. * We demonstrate clinically and statistically significant shifts in glucodynamic response to acute re-exposure to a single cigarette, leading us to conclude that active smokers should be advised against inhaled insulin therapy until smoking abstinence is stable. * Additionally, these results are also the first to demonstrate an apparent independent effect of nicotine replacement therapy on insulin exposure and glucodynamic response.


OBJECTIVE
To explore the effects of smoking cessation and acute smoking re-exposure on the pharmacokinetic (PK) and glucodynamic (GD) profiles of AIR inhaled insulin (AIR Insulin) with or without nicotine replacement therapy (NRT).


METHODS
Nondiabetic smokers (n = 24) with normal pulmonary function completed a two-phase (four-period), open-label, randomized euglycaemic clamp study. During the initial study phase, subjects underwent glucose clamps following AIR Insulin dosing, shortly after smoking, 8-12 h after smoking, or following subcutaneous insulin lispro shortly after smoking. AIR Insulin PK and GD were again assessed during and after a 4-week smoking-cessation period with or without NRT. In the last study period, subjects smoked one cigarette shortly before final AIR Insulin dosing and glucose clamp, to study the effect of acute smoking re-exposure on inhaled insulin PK and GD.


RESULTS
Compared with the preceding active smoking phase, the administration of AIR Insulin in nondiabetic subjects undergoing a 4-week period of smoking abstinence resulted in a decrease in PK and GD of approximately 25% (P = 0.008 for both), an effect which was greater in subjects using NRT. Following rechallenge with a single cigarette (without NRT), GD response to AIR Insulin increased significantly (P = 0.006) towards precessation levels, relative to smoking abstinence. In subjects using NRT, however, the increase in GD was less pronounced.


CONCLUSIONS
Smoking, smoking cessation and acute re-exposure with a single cigarette are associated with clinically significant alterations in AIR Insulin pharmacokinetics and glucodynamics. AIR Insulin should not be used by smokers or those at risk for recidivism.
Pan
Alan X
AX
Lilly-NUS Centre for Clinical Pharmacology Pte Ltd, Singapore. axp@lilly.com
de la Peña
Amparo
A
Yeo
Kwee P
KP
Chan
Clark
C
Loh
Mei T
MT
Wise
Stephen D
SD
Silverman
Bernard L
BL
Muchmore
Douglas B
DB
D000042:Absorption / Q000502:physiology; D000280:Administration, Inhalation; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D004812:Epidemiologic Methods; D005260:Female; D015309:Glucose Clamp Technique / Q000379:methods; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D012907:Smoking / Q000097:blood*; D016540:Smoking Cessation; D016896:Treatment Outcome
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin