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Pharmacodynamics of Antivirals 2991Plasma D4T, mg/L-7-4-10 510 15 20 25Times in HoursFIGURE 5 The concentration–time profile for stavudine in the hollow fiber unit is displayed for a1 mg/(kg day) dose administered either as a continuous infusion or as a 0.5 mg/kg administeredevery 12 hours. The AUCs developed are identical. The ability to suppress viral replication wasidentical for the regimens.stavudine, or diphosphate for prephosphorylated compounds such as tenofovir).It is clear from Figures 6 and 7 that there is full effect at 0.5 mg/kg every 12 hours,irrespective of starting challenge. At half the exposure (0.25 mg/kg q12hr), there isa hint of loss of control late in the experiment. Finally, at 0.125 mg/kg q12hr, thereis no discernible antiretroviral effect.HIV-1 protease inhibitors have also been examined in this system. The firstto be examined was the early Abbott inhibitor A-77003. This drug was a proof-ofprincipleagent and was administered intravenously as a continuous infusion.Consequently, the hollow fiber evaluation was performed as a continuous infusion.When protein binding was taken into account, the concentrations required foreffect were above those tolerable clinically. Consequently, the drug was predictedto fail. Indeed, an extensive phase I/II evaluation came to this conclusion(9,10).The next protease inhibitor evaluated was amprenavir (141W94). Here (11),time > EC-90 was demonstrated to be the pharmacodynamically linked variable.Dosing intervals of q12hr and q8hr with matching AUCs were compared to continuousinfusion of the same AUC. Continuous infusion provided the most robustviral control, followed closely by q8hr dosing. Every 12-hour dosing lost a significantfraction of the control of viral turnover. This outcome was to be expected, asHIV-1 protease inhibitors are reversible inhibitors, freely moving across cell membraneswithout the requirement for energy or a transporter, and do not requireactivation (phosphorylation) for effect as the nucleoside analogs do.A third protease inhibitor was examined, the potent once-daily PI atazanavir(BMS 232632) (12). In addition to the hollow fiber unit evaluation, the techniqueof Monte Carlo simulation was also brought to bear on the outcome of theseexperiments.
300 DrusanoA2520p24 pg/ml(thousands)15105B0251 2 3 4 5 6 7 8 9 10Days p.i.DNA copies per μg DNA (Thousands)201510501 2 3 4Days p.i.5 6 7FIGURE 6 Panel a displays the increase in p24 output over time in a hollow fiber tube that wasan untreated control [&], in a treated (0.5 mg/kg q12hr) tube where 1/1000 cells were chronicallyHIV-infected at start [&] or where 1/100 cells were HIV-infected at start [^]. Panel b showsnumbers of HIV deoxyribonucleic acid copies in treated and untreated hollow fiber units.
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viContents12. Streptogramins and Ox
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viiiContributorsElizabeth D. Hermse
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2 Craigconcentrations. With this pa
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4 Craigaminoglycosides decreases an
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6 CraigLog 10 CFU/Thigh at 24 hours
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8 Craig10080CephalosporinsPenicilli
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10 Craig50Cephalosporins40T>MIC (%)
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12 Craigor fluoroquinolones has a p
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14 CraigTABLE 3 Pharmacodynamic and
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16 Craig14. Andes D, van Ogtrop M.
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18 Craig55. Heffelfinger JD, Dowell
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2 Applying Pharmacodynamics for Sus
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Applying Pharmacodynamics for Susce
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≥Applying Pharmacodynamics for Su
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Section II: Non-clinical Models of
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In Vitro Dynamic Models as Predicti
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4 Animal Models of Infection for th
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Animal Models of Infection for the
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5 The Predictive Value of Laborator
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Predictive Value of Laboratory Test
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130 Tozuka and Murakawacharacterist
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132 Tozuka and Murakawa(cephem, oxa
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134 Tozuka and MurakawaInfusion pha
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136 Tozuka and Murakawapoorly into
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138 Tozuka and Murakawasix hours (3
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140 Tozuka and Murakawadosing inter
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142 Tozuka and MurakawaIntestinal b
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144 Tozuka and Murakawa16. Tozuka Z
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146 Tozuka and Murakawa59. Nicolau
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148 Kim and Nicolauand 23S) and fro
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150 Kim and Nicolaudetectable amino
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152 Kim and Nicolauactivity (26). B
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154 Kim and Nicolaucalculated as th
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156 Kim and Nicolauoverestimate of
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158 Kim and Nicolauit will likely m
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160 Kim and Nicolautrough concentra
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162 Kim and NicolauTABLE 1 Selectio
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164 Kim and NicolauConcentration (
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166 Kim and NicolauAdoption of cont
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168 Kim and Nicolau18. Swenson C, C
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170 Kim and Nicolau61. Karlowsky J,
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172 Kim and Nicolau103. Beaubien AR
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174 Kim and Nicolau146. Marik PE, L
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8 QuinolonesPaul G. AmbroseInstitut
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Quinolones 179876Log 10 CFU/mL54321
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Quinolones 1811.0Probability of era
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Quinolones 183100Efficacy (Percent
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Quinolones 1855040A30201040B302010N
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Quinolones 1878. Ambrose PG, Grasel
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9 Glycopeptide PharmacodynamicsEliz
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Glycopeptide Pharmacodynamics 191Va
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Glycopeptide Pharmacodynamics 193re
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Glycopeptide Pharmacodynamics 195es
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Glycopeptide Pharmacodynamics 197fr
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Glycopeptide Pharmacodynamics 199va
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Glycopeptide Pharmacodynamics 201Va
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Glycopeptide Pharmacodynamics 203TA
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Glycopeptide Pharmacodynamics 205re
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Glycopeptide Pharmacodynamics 207co
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Glycopeptide Pharmacodynamics 209RE
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Glycopeptide Pharmacodynamics 211pa
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Glycopeptide Pharmacodynamics 21386
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Glycopeptide Pharmacodynamics 21513
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218 Jain et al.the polypeptide (P)
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220 Jain et al.1999-2000), all S. p
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222 Jain et al.azalides (7,8). In a
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224 Jain et al.age 65 years or more
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226 Jain et al.cross-resistance, bo
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228 Jain et al.35. Strigl S, Roblin
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230 Jain et al.77. Mandell LA, Bart
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232 Hermsen and RotschaferWhile met
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234 Hermsen and Rotschaferdisulfira
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236 Hermsen and Rotschafer3. George
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12 Streptogramins and Oxazolidinone
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Streptogramins and Oxazolidinones 2
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Page 290 and 291: TABLE 1 Plasma and Intracellular Ph
Page 292 and 293: The Clinical Pharmacology of Nucleo
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Page 305 and 306: 296 DrusanoConsequently, in this ch
Page 307: 298 Drusanolinear function. Finally
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Page 315 and 316: 306 DrusanoWeighted Residuals201816
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Page 319 and 320: 310 DrusanoA600500Mean CD4 over 24
Page 321 and 322: 312 DrusanoTABLE 2 In Vitro Assessm
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Page 325 and 326: 316 Andesmixture of phosphatidylcho
Page 327 and 328: 318 AndesTABLE 1 Amphotericin B Pha
Page 329 and 330: 320 AndesIn vivo time kill studies
Page 331 and 332: 322 AndesA 88CR 2 = 93% R 2 8= 61%7
Page 333 and 334: 324 Andes8. Diekema DJ, Messer SA,
Page 335 and 336: 326 Andes51. Clemons KV, Sobel RA,
Page 337 and 338: 328 Moutonbelow). In 1952, Jerchel
Page 339 and 340: 330 Mouton100Vd3.080t 1/22.5t 1/2 (
Page 341 and 342: 332 Moutontriazoles with values up
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Page 347 and 348: 338 MoutonTABLE 4 Comparative Susce
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Page 353 and 354: 344 Moutonet al. (107). The efficac
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350 Mouton52. Purkins L, Wood N, Gr
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352 Mouton91. Breuker I, Meis JF, V
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18 Glucan Synthase InhibitorsTawand
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Glucan Synthase Inhibitors 357AEchi
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Glucan Synthase Inhibitors 359SUSCE
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Glucan Synthase Inhibitors 36180% m
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Glucan Synthase Inhibitors 363TABLE
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Glucan Synthase Inhibitors 36565Cas
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Glucan Synthase Inhibitors 367appro
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Glucan Synthase Inhibitors 36910025
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Glucan Synthase Inhibitors 371TABLE
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Glucan Synthase Inhibitors 373inter
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Glucan Synthase Inhibitors 3755. Se
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Glucan Synthase Inhibitors 37746. S
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Section VI: Antimalarial Agents19 A
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Antimalarial Agents 381thereby chem
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Antimalarial Agents 383Atovaquone-P
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Antimalarial Agents 385TABLE 1 Sing
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Antimalarial Agents 387relationship
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TABLE 2 Summary of Pharmacokinetic
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Antimalarial Agents 39115Plasma qui
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Antimalarial Agents 393population k
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Total parasite burdenAntimalarial A
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Antimalarial Agents 397are not impo
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Antimalarial Agents 399Total parasi
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Antimalarial Agents 40110 12Total p
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Antimalarial Agents 403parasite dev
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Antimalarial Agents 405treatment or
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Antimalarial Agents 40741. White NJ
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Antimalarial Agents 40985. Simpson
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412 Drusanowell but the end point d
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414 DrusanoHIV copy number change (
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416 Drusanoalso indicates that the
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418 DrusanoPopulation Pharmacokinet
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420 DrusanoProbability1.000.900.800
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422 DrusanoASurvivor function Survi
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424 Drusano(B)1.00Levofloxacin 1000
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426 DrusanoAConcentration (mg/L)B99
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428 DrusanoTABLE 3 Paradigm for the
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430 Drusano20. Lindstrom M, Bates D
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21 Application of Pharmacokinetics
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Application of Pharmacokinetics and
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22 Modeling of Toxicities Due to An
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Modeling of Toxicities Due to Antib
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Section VIII: Pharmacodynamics and
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Pharmacodynamics and Antibacterial
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488 Coleman et al.incorporate consi
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490 Coleman et al.Evaluations are m
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492 Coleman et al.external validity
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494 Coleman et al.A pharmacoeconomi
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496 Coleman et al.with antibiotic A
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498 Coleman et al.TABLE 3 Reporting
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500 Coleman et al.specific populati
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502 Coleman et al.determine the rob
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IndexAbacavir, 279-284, 287-291, 42
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Index 507[Antibiotic pharmacodynami
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Index 509[Azoles]in vivo, concentra
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Index 511[Glycopeptide pharmacodyna
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Index 513Moxifloxacin, 53Mueller Hi
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Index 515[Quinolones]antimicrobial
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About the EditorsCHARLES H. NIGHTIN
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