OIII-B-3Variation in the α2B adrenergic receptor and its relationship to desensitization of...
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OIII-B-3 VARIATION IN THE 2B ADRENERGIC RECEPTOR AND ITS RELATIONSHIP TO DESENSITIZATION OF VASCULAR RESPONSE TO AGONIST IN VIVO. M. Muszkat, MD, G. G. Sofowora, MD, D. Kurnik, MD, J. Solus, PhD, L. Jiang, MS, S. M. Williams, PhD, E. P. Dawson, Bsc, H. G. Xie, MD, PhD, P. A. Harris, PhD, A. J. Wood, MD, C. M. Stein, MD, Vanderbilt Univer- sity, Bioventures Inc, Nashville, TN. AIMS: Vascular 2B adrenergic receptor (ADRA2B) mediate vasoconstriction and contribute to peripheral regulation of vascular tone. In vitro, ADRA2B undergoes agonist-induced desensitization and a common genetic variation, 301-303 deletion, was associated with loss of desensitization. We previously characterized variation in ADRA2B and observed 24 variant sites. This study examines the hypothesis that the 301-303del or other variants alter vascular desen- sitization in response to the selective ADRA2 agonist, dexmedeto- midine (D) in vivo. METHODS: Venoconstriction in response to D (0.01-1000 ng/ min) was measured in the dorsal hand vein using a linear variable differential transformer in 40 healthy subjects (age 18-45 yrs). On a separate day, the dose that had caused 50% constriction in the dose-response study was infused for 180 min and response measured. The area under the curve for response, normalized to the initial response (nAUC) was calculated. 5812 bp of contiguous sequence of ADRA2B were examined by bidirectional sequencing, and relation- ship of ADRA2B variants to nAUC determined. RESULTS: Six variants (1 promoter, 3 coding, 2 3’ UTR) were found with an allele frequency 5%. nAUC was 0.93 0.22 (meanSD). 301-303del or other common variant did not contribute to variability in nAUC. [Ins/Ins (n22): 0.89 0.23, Ins/del (n11): 0.98 0.24, del/del (n7): 0.98 0.16; pANOVA 0.47]. CONCLUSION: Common variants in ADRA2B do not contribute substantially to ADRA2B vascular desensitization in vivo. OIII-B-4 SYNERGISTIC POLYMORPHISMS OF 1 - AND 2C - ADRENERGIC RECEPTORS AND THE INFLUENCE ON LEFT VENTRICULAR EJECTION FRACTION IN RESPONSE TO - BLOCKER THERAPY IN HEART FAILURE. M. T. Lobmeyer, BSPharm, S. G. Terra, PharmD, Y. Gong, PhD, K. K. Hamilton, MD, D. F. Pauly, MD, PhD, J. H. Patterson, PharmD, K. F. Adams, Jr, MD, R. S. Schofield, MD, J. A. Hill, MD, MS, J. M. Aranda, MD, J. A. Johnson, PharmD, University of Florida, University of North Carolina, Gainesville, FL. BACKGROUND: Polymorphisms in the 2c adrenergic receptor (ADRA2C) and the 1 adrenergic receptor (ADRB1) genes have been suggested to act synergistically in heart failure (HF) risk. We tested their association (and synergism) with -blocker (BB) response in HF. METHODS: Left ventricular ejection fraction (EF) was deter- mined by echocardiography at baseline and after 5-6 months of metoprolol CR/XL therapy in 54 patients with systolic HF. ADRB1 Arg389Gly and ADRA2C 322-325 Insertion/Deletion (Ins/Del) poly- morphisms were determined by pyrosequencing. Linear regression modeling of end of study EF was done with patient age, race, genotypes, HF etiology, spironolactone, digoxin, and furosemide use and final metoprolol CR/XL dose considered in the model. EF re- sponse by genotype was compared by t-tests and ANOVA. RESULTS: Significant predictors of the end study EF were base- line EF, Del-carrier status, Arg389Arg genotype and age. The com- bination of both genotypes (Arg389Arg & Del-carrier) (Gp1) showed the greatest EF change. Adjusting for baseline EF and age, the end study EF of Gp1 was significantly different from the 3 other groups (overall p0.0012) (table). Genotype combination baseline EF (%) end study EF (%) p value vs. Gp1 Arg389Arg & Del-carrier (Gp1) 22 6 34 15 - Arg389Arg & Ins/Ins 24 6 26 7 0.0012 G389 carrier and Del-carrier 24 12 26 15 0.0098 G389 carrier and Ins/Ins 20 6 20 6 0.0001 CONCLUSIONS: Polymorphisms in the ADRB1 and ADRA2C genes synergistically influence the left ventricular reverse remodeling response to -blockers in HF. OIV-A-1 PHARMACOKINETICS AND DOSE OPTIMIZATION OF SELENOMETHIONINE (SLM) AS AN ADJUNCT TO IRINOTE- CAN (CPT-11) THERAPY. P. F. Smith, PharmD, M. Fakih, MD, L. Pendyala, PhD, J. Prey, R. Azrak, PhD, P. Creaven, MD, PhD, Y. M. Rustum, PhD, Roswell Park Cancer Institute, Buffalo, NY. AIM: We previously showed SLM reduces CPT-11 toxicity and improves activity at plasma levels 1200 ng/mL Se in animals. Our aim was to characterize SLM PK and design a dose regimen to achieve this target in pts. METHOD: 13 refractory solid tumor pts enrolled in a Phase I trial of SLM (2200ug Se as SLM PO QD) started 1 wk before dose escalated CPT-11. Intensive plasma PK of Se on d8 of cycle 1 and troughs during therapy. CPT-11 and metabolite (SN38, SN38G) PK determined wks 1 and 4. PK analyzed by compartmental modeling. RESULTS: Se accumulation was slow: 4-6 wks to achieve steady state. Mean (SD) CLt/F and T1/2 of Se after SLM was 0.12 (0.05) L/h and 183 (94)h. CPT-11 biliary index, BIAUC(CPT11.SN38/ SN38G), associated with GI toxicity, was 85% lower after 4 wks SLM vs. wk 1. Simulations were used to design regimens to achieve the 1200 ng/mL target within 7d, before CPT-11. These candidate SLM strategies are being formally tested in an ongoing Phase I trial of fixed dose CPT-11 and dose escalated SLM based on toxicity and [Se]. 16 pts have enrolled: 4/6 achieved the 1200 ng/mL target within 7d after a loading dose of 4000ug SLM BID x7d; 2/6 subjects were within 23 and 14% of the target. Maintenance doses of 3200ug QD maintained 5/6 patients 1200 ng/mL for 3 - 4 months. CONCLUSION: SLM demonstrated a long T1/2, significant and slow accumulation, and may reduce CPT-11 GI toxicity by altering BI. The use of modeling, simulation, and a ‘learn and confirm’ approach to the development of SLM as a therapeutic has improved the ability to evaluate this novel compound rapidly and efficiently. OIV-A-2 GENDER-SPECIFIC DIFFERENCES IN THE PHARMACOKI- NETICS OF RITONAVIR (RTV)-BOOSTED SAQUINAVIR (SQV) IN MEN, WOMEN AND PREGNANT WOMEN. N. H. von Hentig, MD, A. Haberl, MD, S. Klauke, MD, L. Locher, MD, S. Staszewski, MD, S. Harder, MD, Institute for Clinical Pharmacol- ogy, J.W. Goethe-University Hospital, HIV Treatment and Research Unit, J.W. Goethe-University Hospital, IFS Stresemannallee, Private Practice Grueneburgweg, HIV Research and Treatment Unit, J.W.Goethe-University Hospital, Frankfurt/M., Germany. BACKGROUND: SQV/RTV 1000/100mg BID plus nucleos- (t)ide reverse transcriptase inhibitors (NRTI) is a frequently used HIV-therapy during pregnancy. However not much is known about the steady-state pharmacokinetics (PK) of SQV in late pregnancy. OBJECTIVE: To evaluate the plasma exposure of SQV/RTV 1000/100mg BID and possible influencing factors in pregnant women (n14), women (n12) and men (n66). METHODS: Patients performed a standardized 12h-PK assess- ment at steady state. SQV/RTV concentrations were measured by LC/MS/MS. The influence of ethnicity, gender, age, bodyweight and co-medication on Cmin, Cmax; AUCss, CLtot, t1/2 and volume of distribution was analysed in a multiple linear regression analysis by the stepwise deletion of variables. RESULTS: Mean(SD) SQV Cmin, Cmax and AUCss were 524(425)ng/mL, 2639(1406)ng/mL and 18015(10761)ngh/mL for men, 966(574)ng/mL, 3653(2291)ng/mL and 26477(14991) ngh/mL for women and 639(300)ng/mL, 2629(1350)ng/mL and 18448(9152)ngh/mL for pregnant women. The differences be- tween men and women reached statistical significance (Cmin, p.002; Cmax, p .043; AUCss, p.021) The multivariate analysis identified bodyweight (p.003) and body-mass index (p.006) as factors influencing the SQV plasma exposure. CONCLUSIONS: Non pregnant women exhibited higher SQV plasma levels than men and women in late stage of pregnancy. SQV exposure depends on bodyweight and shows a great variability. TDM should therefore be performed frequently. CLINICAL PHARMACOLOGY & THERAPEUTICS 2006;79(2) American Society for Clinical Pharmacology and Therapeutics P31
Transcript of OIII-B-3Variation in the α2B adrenergic receptor and its relationship to desensitization of...
OIII-B-3VARIATION IN THE �2B ADRENERGIC RECEPTOR AND
ITS RELATIONSHIP TO DESENSITIZATION OF VASCULARRESPONSE TO AGONIST IN VIVO. M. Muszkat, MD, G. G.Sofowora, MD, D. Kurnik, MD, J. Solus, PhD, L. Jiang, MS, S. M.Williams, PhD, E. P. Dawson, Bsc, H. G. Xie, MD, PhD, P. A.Harris, PhD, A. J. Wood, MD, C. M. Stein, MD, Vanderbilt Univer-sity, Bioventures Inc, Nashville, TN.
AIMS: Vascular �2B adrenergic receptor (ADRA2B) mediatevasoconstriction and contribute to peripheral regulation of vasculartone. In vitro, ADRA2B undergoes agonist-induced desensitizationand a common genetic variation, 301-303 deletion, was associatedwith loss of desensitization. We previously characterized variation inADRA2B and observed 24 variant sites. This study examines thehypothesis that the 301-303del or other variants alter vascular desen-sitization in response to the selective ADRA2 agonist, dexmedeto-midine (D) in vivo.
METHODS: Venoconstriction in response to D (0.01-1000 ng/min) was measured in the dorsal hand vein using a linear variabledifferential transformer in 40 healthy subjects (age 18-45 yrs). On aseparate day, the dose that had caused 50% constriction in thedose-response study was infused for 180 min and response measured.The area under the curve for response, normalized to the initialresponse (nAUC) was calculated. 5812 bp of contiguous sequence ofADRA2B were examined by bidirectional sequencing, and relation-ship of ADRA2B variants to nAUC determined.
RESULTS: Six variants (1 promoter, 3 coding, 2 3’ UTR) werefound with an allele frequency 5%. nAUC was 0.93� 0.22(mean�SD). 301-303del or other common variant did not contributeto variability in nAUC. [Ins/Ins (n�22): 0.89 �0.23, Ins/del (n�11):0.98 �0.24, del/del (n�7): 0.98 �0.16; pANOVA� 0.47].
CONCLUSION: Common variants in ADRA2B do not contributesubstantially to ADRA2B vascular desensitization in vivo.
OIII-B-4SYNERGISTIC POLYMORPHISMS OF �1- AND �2C-
ADRENERGIC RECEPTORS AND THE INFLUENCE ON LEFTVENTRICULAR EJECTION FRACTION IN RESPONSE TO �-BLOCKER THERAPY IN HEART FAILURE. M. T. Lobmeyer,BSPharm, S. G. Terra, PharmD, Y. Gong, PhD, K. K. Hamilton, MD,D. F. Pauly, MD, PhD, J. H. Patterson, PharmD, K. F. Adams, Jr,MD, R. S. Schofield, MD, J. A. Hill, MD, MS, J. M. Aranda, MD,J. A. Johnson, PharmD, University of Florida, University of NorthCarolina, Gainesville, FL.
BACKGROUND: Polymorphisms in the �2c adrenergic receptor(ADRA2C) and the �1 adrenergic receptor (ADRB1) genes have beensuggested to act synergistically in heart failure (HF) risk. We tested theirassociation (and synergism) with �-blocker (BB) response in HF.
METHODS: Left ventricular ejection fraction (EF) was deter-mined by echocardiography at baseline and after 5-6 months ofmetoprolol CR/XL therapy in 54 patients with systolic HF. ADRB1Arg389Gly and ADRA2C 322-325 Insertion/Deletion (Ins/Del) poly-morphisms were determined by pyrosequencing. Linear regressionmodeling of end of study EF was done with patient age, race,genotypes, HF etiology, spironolactone, digoxin, and furosemide useand final metoprolol CR/XL dose considered in the model. EF re-sponse by genotype was compared by t-tests and ANOVA.
RESULTS: Significant predictors of the end study EF were base-line EF, Del-carrier status, Arg389Arg genotype and age. The com-bination of both genotypes (Arg389Arg & Del-carrier) (Gp1) showedthe greatest EF change. Adjusting for baseline EF and age, the endstudy EF of Gp1 was significantly different from the 3 other groups(overall p�0.0012) (table).
Genotype combinationbaselineEF (%)
end studyEF (%) p value vs. Gp1
Arg389Arg & Del-carrier (Gp1) 22 � 6 34 � 15 -Arg389Arg & Ins/Ins 24 � 6 26 � 7 0.0012G389 carrier and Del-carrier 24 � 12 26 � 15 0.0098G389 carrier and Ins/Ins 20 � 6 20 � 6 0.0001
CONCLUSIONS: Polymorphisms in the ADRB1 and ADRA2Cgenes synergistically influence the left ventricular reverse remodelingresponse to �-blockers in HF.
OIV-A-1PHARMACOKINETICS AND DOSE OPTIMIZATION OF
SELENOMETHIONINE (SLM) AS AN ADJUNCT TO IRINOTE-CAN (CPT-11) THERAPY. P. F. Smith, PharmD, M. Fakih, MD, L.Pendyala, PhD, J. Prey, R. Azrak, PhD, P. Creaven, MD, PhD, Y. M.Rustum, PhD, Roswell Park Cancer Institute, Buffalo, NY.
AIM: We previously showed SLM reduces CPT-11 toxicity andimproves activity at plasma levels � 1200 ng/mL Se in animals. Our aimwas to characterize SLM PK and design a dose regimen to achieve thistarget in pts.
METHOD: 13 refractory solid tumor pts enrolled in a Phase I trialof SLM (2200ug Se as SLM PO QD) started 1 wk before doseescalated CPT-11. Intensive plasma PK of Se on d8 of cycle 1 andtroughs during therapy. CPT-11 and metabolite (SN38, SN38G) PKdetermined wks 1 and 4. PK analyzed by compartmental modeling.
RESULTS: Se accumulation was slow: 4-6 wks to achieve steadystate. Mean (SD) CLt/F and T1/2 of Se after SLM was 0.12 (0.05) L/hand 183 (94)h. CPT-11 biliary index, BI�AUC(CPT11.SN38/SN38G), associated with GI toxicity, was 85% lower after 4 wksSLM vs. wk 1. Simulations were used to design regimens to achievethe 1200 ng/mL target within 7d, before CPT-11. These candidateSLM strategies are being formally tested in an ongoing Phase I trialof fixed dose CPT-11 and dose escalated SLM based on toxicity and[Se]. 16 pts have enrolled: 4/6 achieved the 1200 ng/mL target within7d after a loading dose of 4000ug SLM BID x7d; 2/6 subjects werewithin 23 and 14% of the target. Maintenance doses of 3200ug QDmaintained 5/6 patients 1200 ng/mL for 3 - 4 months.
CONCLUSION: SLM demonstrated a long T1/2, significant andslow accumulation, and may reduce CPT-11 GI toxicity by alteringBI. The use of modeling, simulation, and a ‘learn and confirm’approach to the development of SLM as a therapeutic has improvedthe ability to evaluate this novel compound rapidly and efficiently.
OIV-A-2GENDER-SPECIFIC DIFFERENCES IN THE PHARMACOKI-
NETICS OF RITONAVIR (RTV)-BOOSTED SAQUINAVIR(SQV) IN MEN, WOMEN AND PREGNANT WOMEN. N. H. vonHentig, MD, A. Haberl, MD, S. Klauke, MD, L. Locher, MD, S.Staszewski, MD, S. Harder, MD, Institute for Clinical Pharmacol-ogy, J.W. Goethe-University Hospital, HIV Treatment and ResearchUnit, J.W. Goethe-University Hospital, IFS Stresemannallee, PrivatePractice Grueneburgweg, HIV Research and Treatment Unit,J.W.Goethe-University Hospital, Frankfurt/M., Germany.
BACKGROUND: SQV/RTV 1000/100mg BID plus nucleos-(t)ide reverse transcriptase inhibitors (NRTI) is a frequently usedHIV-therapy during pregnancy. However not much is known aboutthe steady-state pharmacokinetics (PK) of SQV in late pregnancy.
OBJECTIVE: To evaluate the plasma exposure of SQV/RTV1000/100mg BID and possible influencing factors in pregnant women(n�14), women (n�12) and men (n�66).
METHODS: Patients performed a standardized 12h-PK assess-ment at steady state. SQV/RTV concentrations were measured byLC/MS/MS. The influence of ethnicity, gender, age, bodyweight andco-medication on Cmin, Cmax; AUCss, CLtot, t1/2 and volume ofdistribution was analysed in a multiple linear regression analysis bythe stepwise deletion of variables.
RESULTS: Mean(�SD) SQV Cmin, Cmax and AUCss were524(�425)ng/mL, 2639(�1406)ng/mL and 18015(�10761)ng�h/mLfor men, 966(�574)ng/mL, 3653(�2291)ng/mL and 26477(�14991)ng�h/mL for women and 639(�300)ng/mL, 2629(�1350)ng/mL and18448(�9152)ng�h/mL for pregnant women. The differences be-tween men and women reached statistical significance (Cmin,p�.002; Cmax, p� .043; AUCss, p�.021) The multivariate analysisidentified bodyweight (p�.003) and body-mass index (p�.006) asfactors influencing the SQV plasma exposure.
CONCLUSIONS: Non pregnant women exhibited higher SQVplasma levels than men and women in late stage of pregnancy. SQVexposure depends on bodyweight and shows a great variability. TDMshould therefore be performed frequently.
CLINICAL PHARMACOLOGY & THERAPEUTICS2006;79(2) American Society for Clinical Pharmacology and Therapeutics P31
