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`i HARMACOLOGY
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`&THERAPEUTICS
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`COPYRIGHT © 1993 BY MOSBY - YEAR BOOK, INC.
`
`VOLUME 53 NUMBER 2
`
`MARCUS M. REIDENBERG, MD Editor
`
`lPPEARING IN THIS ISSUE .~
`J Abstracts of papers presented at the Ninety-founh Annual Meeting of the
`American Society for Clinical Pharmacology and Therapeutics
`
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`PUBLISHED AT ST. LOUIS, MISSOURI 63146-3318 BY MOSBY-YEAR BOOK, INC.
`ISSN 0009-9236
`
`
`1 of 3
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1030
`
`

`

`FEBRU-. - -•993
`
`'
`
`COPYRJGHT © 1993 BY MOSBY- YEAR BOOK, lNC.
`
`~•J Mosby
`I' n Year Book
`
`TABLE OF CONTENTS
`AMERICAN SOCIETY FOR CLINICAL PHARMACOLOGY
`AND THERAPEUTICS
`
`135 Abstracts of papers presented at the Ninety-fourth Annual Meeting,
`The Hilton Hawaiian Village, Honolulu, Hawaii, March 24-26, 1993
`
`242 Index to abstract authors and subjects
`
`Information to authors cm pages 7A, BA, and 9A
`
`Volume 53, Number 2, Fcbuary 1993. CUNICAL PHAl\MACOLOGl' & THERAPEUTICS (ISSN 0009-9236). Published monthly (six issues per volume, two vol(cid:173)
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`Cover 2
`
`FEBRUARY 1993
`
`
`2 of 3
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1030
`
`

`

`CLINICAL PHARMACOLOGY & THERAPEUTICS
`VOLUME 53. NUMBER 2
`
`American Society for Clinical Phannacology and Therapeutics 145
`
`PI-40
`PHARMACOKINETICS (PK) OF ESMOLOL
`(ES)
`IN
`PEDIATRIC POST-CARDIAC SURGERY PATIENTS. DB
`Wiest. PhannD*, SS Gamer, PhannD*, WE Uber, PhannD*,
`RM Sade*, M.D., PC Gillette, M.D.*. Depts. of Clinical
`Phannacy, Surgery, & Pediatric Cardiology, Med. Univ. of
`South Carolina, Charleston, SC.
`The PK and hemodynamics of ES were investigated in 8
`children (1.3-148 mo.; median: 29.6 mo.) with acute post(cid:173)
`cardiac surgical hypertension. Sodium nitroprusside, 2-4
`µg!kglmin (mean:3.6), was discontinued 6-12 min (mean:
`9 min) prior to starting ES in all patients. ES given by
`continuous infusion was titrated to achieve blood pressure
`(BP) < 90lh percentile for age. ES blood samples (Cp) were
`obtained during and post infusion. Arterial BP, mean
`arterial pressure (MAP) and heart rate (HR) were
`simultaneously recorded with each sample time. ES was
`analyzed by HPLC. ES concentration-time profiles were
`analyzed using noncompartmental analysis. Regression
`analysis was used to determine significant associations
`(p<.05) between the following: 1) Cp and mean %
`reduction in MAP and HR; 2) age and PK parameters.
`Maximum dose required to control BP was 300-1000
`µg/kglmin (mean: 625; median: 500). The PK results
`revealed the following: CL (mVkg/min)= 134 ± 73.9; V,.
`(L/kg)=l.02 ± 0.80; t,11 (min)= 4.3 ± 2.1. There was a
`significant correlation (p<.001) between ES Cp and o/o
`reduction in MAP. ES was effective in controlling acute
`post-operative hypertension in 8/8 patients.
`
`PI-41
`DRUG DELNERY OF METERED DOSE INHALERS (MDI)
`VIA PEDIATRIC ENDOTRACHEAL 11JBES (ETf). SS Gamer.
`PharmD*, DB Wiest, PharmD*, & JW Bradley, RTT*. Depts.
`of Clinical Pharmacy, Pediatrics, & Respiratory Therapy,
`Med. Univ. of South Carolina, Charleston, SC.
`Drug delivery by MDI in intubated children has not been
`investigated. This in-vitro study assessed albuterol (AL)
`delivery by MDI via pediatric ETT. The model consisted of
`a Hamilton Veo~ ventilator, pediatric breathing circuit,
`Aerovent9 spacing chamber or Airlife(f MDI adapter
`connected to an AL MDI canister, and ETT (4,5, or 6mm)
`cut to equal lengths (19cm). The ETT tip was fitted to an
`in-line stainless steel filter holder with a 0.3µ NE filter.
`Ten canisters were actuated 2 times (2000 µg) into dry
`(4,5,and 6mm ETf) and humidified air (4 and 6mm ETI')
`in triplicate. Percentage AL delivery was determined by
`weighing the filter prior to assembly and following drug
`administration (balance sensitivity: ± 20µg). Significant
`differences (a=0.05) were determined by ANOVA and
`student's t test. Percentage AL delivery in dry air with and
`without the spacer was: 4mm: 15.5 ± 0.87 vs. 7.5 ± 1.32,
`5mm: 15.8 ± 1.06 vs. 6.5 ± 0, 6mm: 15.2 ± 1.26 vs. 7.7 ±
`0.29. In humidified air, delivery was: 4mm: 2.5 ± 0.84 vs.
`1.3 ± 0.94 and 6mm: 5.3 ± 1.44 vs. 2.4 ± 1.36. These
`results indicate ETT size does not influence drug delivery.
`AL delivery was significantly improved with the Aeroven~
`spacer (mean:112%) and dry air (mean: 351%) with each
`ETT size studied (p<0.01).
`
`PI-42
`PAIN-FEVER PHARMACOKINETICS/DYNAMICS
`(PK/PD) IN CHILDREN . M• Kellev. MD. J.
`Edge, MS, s. Suzuki, MD,PhD, P. Walson,
`MD, Div. Clin. Pharin/Tox, Ohio state
`Univ., Children's Hosp., Columbus, OH.
`The PK/PD of acetaminophen (APAP) and
`ibuprofen (IBU) were studied in 20
`febrile children {5-12 yrs) with sore
`throat pain. The vital signs, 3 pain
`measures (faces, visual analog and
`poker-chip scales) and blood samples
`were collected at intervals for 10 hours
`after either placebo, 5 or 10 mg/kg IBU
`liquid or 15 mg/kg APAP elixir. Despite
`small numbers, PK/PD analyses (MKMODEL,
`Holford) revealed excellent IBU PK
`behavior with a sigmoid E,.,.. temperature
`fit for the 10 mg/kg IBU. All pain
`responses occurred earlier than temper(cid:173)
`ature, especially chips (Keq=0.016), and
`best fit a linear model as did APAP and
`IBU 5 mg/kg.
`KA
`Vd CL
`Keq
`EC50
`DRUG
`min-1 ml ml/min min-1 mg/L
`IBU5
`.018
`187 0.89
`.004
`IBUlO
`.075
`200 1.45
`.005
`APAP
`.031
`867 3.90
`.018
`Such data may be useful to explain or
`predict clinical responses and to
`generate testable hypotheses.
`
`10.8
`
`PI-43
`EFFECTIVE IRON CHELATION USING THE ORAL
`IRON CHELATOR, 1,2-DIMETHYL-3-HYDROXYPYRID-
`4-0NE (LI), IN HOMOZYGOUS B-THALASSEMIA
`MAJOR (HBT) PATIENTS (PTS). D Matsui MP*, N.
`Olivieri MD*, M. Berkovitch MD*, D. Templeton MD*, I.
`Wanless MD*. L. Blendis MD*, P. Liu MD*, G. Koren MD,
`The Hospital for Sick Children, Toronto, Canada.
`Decause iron overload and subsequent organ dysfunction
`results from regular transfusions in HBT pts, effective iron
`chelation is essential. The oral iron chelator, Ll, is currently
`being studied. 15 pts aged 20.6±4.6 (mean±SD) years were
`treated with LI, 75-100 mg/kg/day, for a period of 21.8±8.2
`months (mos). Compliance (% of prescribed doses taken)
`assessed by the Medication Event Monitoring System (MEMS)
`during the initial 137.9±16.4 days of therapy in the first 7 pts
`was 91.7±.7.4%. After 16.0±.7.3 mos of LI therapy.
`compliance in the 15 pts remained acceptable at 81.3±14.7%.
`Serum ferritin (SF) has decreased from an initial value of
`4370±4014 µg/L to 2833±2142 µg/L (p=0.018). Urinary
`iron excretion was 0.6±0.4 mg/kg/day. Compared to pts
`receiving subcutaneous (sc) DFO matched for SF, a decline in
`SF was noted in 10/14 Li-treated pts and in 3/14 DFO-treated
`pts over a mean period of 20 mos (Fisher's Exact p=0.021 ).
`Preliminary analysis suggests a decrease in iron by Prussian
`blue staining in follow-up liver biopsies in some pts as well as
`a reduction of cardiac iron as demonstrated by magnetic
`resonance imaging in 1 pt with established cardiac disease.
`Joint pain and swelling have been noted in 3 pts all of whom
`continue on LI. These data suggest that LI is a promising
`agent, superior or at least comparable to sc DFO, which may
`be useful in the removal of excess tissue iron.
`
`
`3 of 3
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1030
`
`