Transcript Document

S. Balakrishnan
Department of Pharmacology,
Pondicherry Institute of Medical
Sciences
Absorption
 How long it takes after absorption till drug is
detectable? (lag time or tlag).
 How long it takes before peak – serum or
plasma concentration are achieved (tmax).
 What is the peak serum concentration? (Cmax)
Absorption problems 1
Vomiting patient
Ketoconazole needs acid
Patients on proton pump inhibitors
(PPI), H2 blockers
Take with Coca Cola
Absorption problems-2
Quinolones (ciprofloxacin)
Bind to antacids, sucralfate
Solution: PPI or H2 blocker
Didanosine (ddI) unstable in acid; so:
antacid in the tablet
Drugs taken with (out) food
Distribution
Changing Vd
Gentamicin distributes into space resembling
extracellular fluid (ECF)
ECF larger in shock, drops with recovery
Gentamicin levels lower in shock, rise with
recovery
Limited distribution-1
Most antibiotics well distributed, but ...
Not always intracellular
Not always to:
Central nervous system
Eye
Prostate
Placenta
Breast milk
Bone
Limited distribution-2
Meningitis: Higher doses to get adequate
CNS levels
Prostatitis: Prefer trimethoprimsulfamethoxazole, quinolones
Intracellular penetration
pH- only basic drugs penetrate
Beta lactams ansd AGs- NO
Quinolones and macrolides-YES
Distribution to placenta & breast
milk
Hard to predict
Practical matter: look up data on a drug
Plasma protein binding
Unbound drug exerts effect.
Unbound drug diffuses into extra vascular
sites.
Slows rate of elimination - & t½ - longer
dosing interval.
Significant only if > 80%
Extensive protein binding
“Good”: Allows slow, steady release of
heavily bound drug, e.g. ceftriaxone
“Bad”: since less “free” drug available for
bacteria, e.g. Ceftriaxone
Reality: Only one factor
Protein binding perinatal issue
Sulfonamide displaces unconjugated
bilirubin from serum protein
Perinatally, high unbound bilirubin causes
kernicterus & brain damage
Don’t use sulfonamides in 3rd trimester,
neonate
Biotransformation
Phase I
Phase II
Biotransformation: CYP 450
Often hepatic microsomal enzymes (CYP
450)
Rates vary up to 6-fold from one person to
the next
Enzymes genetically determined
Biotransformation: HIV & TB
Rifampin (for TB) induces CYP450 3A4 &
reduces levels of indinavir (for HIV)
Indinavir inhibits CYP450 3A4 & increases
levels of rifampin
Solution: Low dose rifabutin, high dose
indinavir
Biotransformation: ketoconazole,
erythromycin
Ketoconazole, erythomycin inhibit CYP450
3A4
Slows metabolism of cisapride, levels rise,
causes torsade de pointes, death
Cisapride highly restricted
Bioavailability
IV to oral switch
Elimination
Renal vs non renal clearance
Elimination t1/2
General concept: Elimination t1/2
Half-life
Time for serum concentration to fall 50%
Constant if a person is stable
Varies from person to person
Concentration- time curve
Extravascularconcentration
Extracellular sites reached via diffusion
from blood
Intracellular fluid
Extracellular sites with restrictive
barriers
Urine
General concept: Clearance
Quantitative measure of body’s ability to
eliminate the drug
Includes various forms of excretion
Antimicrobial concept: MIC, MBC
MIC: Minimum inhibitory concentration
(to inhibit growth in vitro)
MBC: Minimum bactericidal concentration
(to kill in vitro)
MIC90: Inhibits 90% of strains
Break point
Is in part concentration which can be
achieved at the site of infection
Susceptible: MIC < breakpoint
Resistant: MIC > breakpoint
Post-antibiotic effect
Persistence of effect (inhibition of
growth or killing) after drug removed (or
level below MIC)
“PAE” + pharmacokinetics affects dosing
strategy
Post-antibiotic effect
 Post antibiotic sub – MIC effects
 Post antibiotic – leukocyte effects
Important
PK/PD Parameters
Parameters
Important PK/PD
Time above
MIC:
Proportion of the
dosing interval
when the drug
concentration
exceeds the MIC
Antibiotic concentration
(ug/ml)
8
6
4
Drug A
Drug A
Drug B
Drug B
2
B
B
0
A
Time above MIC
Time
AUC/MIC
is the ratio of the
AUC to MIC
Peak/MIC
is the ratio of the
peak
concentration to
MIC
Antibiotic
concentration
Important PK/PD Parameters
Area under the curve
over MIC
PEAK
Time
PK/PD and Antimicrobial Efficacy
 2 main patterns of bacterial killing
 Concentration dependent
 Aminoglycosides, quinolones, macrolides,
azalides, clindamycin, tetracyclines,
glycopeptides, oxazolidinones
 Correlated with AUC/MIC , Peak/MIC
 Time dependent with no persistent effect
 Beta lactams
 Correlated with Time above MIC(T>MIC)
Goal of therapy based on PK/PD
Pattern of
Activity
Antimicrobials
Goal of therapy and
relevant PK/PD
Parameter
Concentration AGs, Quinolones,
dependent
Daptomycin, ketolides,
killing
Macrolides, azithro-mycin,
clindamycin,streptogramines
,tetracyclines, glycopeptides,
oxazolidinones
Maximise concentrations;
AUC/MIC, peak/MIC
Use high doses; daily
dosing for some agents
Time
Beta lactams
dependent
killing with no
persistent
effects
Maximise duration of
exposure; T>MIC
Use more frequent dosing;
longer infusion times
including continuous
infusion
Pattern of Activity
Antibiotics
Goal of
Therapy
PK/PD
Parameter
Type I
Concentrationdependent killing and
Prolonged persistent
effects
Aminoglycosides
Daptomycin
Fluoroquinolones
Ketolides
Maximize
24h-AUC/MIC
concentratio
Peak/MIC
ns
Type II
Time-dependent killing
and
Minimal persistent
effects
Carbapenems
Cephalosporins
Erythromycin
Linezolid
Penicillins
Maximize
duration of
exposure
T>MIC
Type III
Time-dependent killing
and
Moderate to prolonged
persistent effects.
Azithromycin
Clindamycin
Oxazolidinones
Tetracyclines
Vancomycin
Maximize
amount of
drug
24h-AUC/MIC
Magnitude of PK/PD measures predictive of efficacy
for select antibiotic classes versus some pathogens
Drug
PK/PD variable
Magnitude of variable
correlated with efficacy
Beta lactams
Time > MIC
>40-50% of dosing
interval
Quinolones vs Gram –
ve bacteria
24- hour AUC:MIC
>90-125
Quinolones vs S.
24-hour AUC:MIC
>30-40
pneumoniae
Aminoglycoside pharmacodynamics
in vivo
Vancomycin Outcome vs 24h-AUC/
MIC ratio
24hAUC/MIC
ratio
Satisfactory
Unsatisfactory
< 125
4 (50%)
4
> 125
71 (97%)
2
Fluoroquinolone PK/PD vs S.
pneumoniae
24h-AUC/MIC
ratio
Microbiological
Response
< 33.7
(64%)
> 33.7
(100%)
PK/PD of beta-lactams and
macrolides in otitis media
Concentration dependent
killing….azithromycin
•24 hour AUC/ 25-immunocompetent patients
•24 hour AUC/ 125- immnocompromised patients
•24 hour AUC mg.h/ L -3 mg.h/L
•Macrolide susceptible S.pneumoniae MIC90 0.12 mg/L
•H. Influenzae MIC90 1-2mg/L
•Macrolide resistant S. pneumoniae MIC90 >8mg/L
PK/PD breakpoints of parenteral beta-lactams based
on serum concentrations present for >40-50% of
dosing regimens shown and MIC90 values of isolates of
S. pneumoniae
Drug
Dosing regimen
S.Pneumonia PK/PD
e MIC90 mg/L breakpoint
mg/L
Pen G
2 X 106 U qid
4
4
Ampicillin
Cefuroxime
Cefotaxime
Ceftriaxone
1 g qid
0.75 g tid
1 g tid
1 g qd
4
8
2
2
2
4
2
2
Cefepime
Ceftazidime
Meropenem
1 g bid
1 g tid
0.5 g tid
4
32
2
4
8
1
Dosage Adjustment Needed in
Renal Impairment I
Acyclovir
ethambutol
aminoglycosides,
Penicillins (except
antistaph)
aztreonam,
Quinolones
cephalosporins (except cefaperazone &
ceftriaxone)
clarithromycin,
Carbapenems
Dosage Adjustment Needed in
Renal Impairment II
daptomycin,
Vancomycin
doripenem,
emtricitabine,
famiclovir,
ertapenem,
flucytosine,
ganciclovir,
imipenem,
meropenem,
lamivudine,
foscarnet,
fluconazole,
C/I in renal failure
Methanamine
Nalidixic acid
Nitrofurantoin
Sulfonamides
Tetracyclines except doxy & minocycline
Dosage adjust in hepatic impairment
Chloramphenicol
Clindamycin
Erythromycin
Metronidazole
Tigecycline