SALIVARY, PROTEIN
UNBOUND AND TOTAL
PLASMA CONC OF
RIFAMPICIN
HADIJA H SEMVUA
KCRI_PhD SYMPOSIUM 2013
4/8/2015
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Outline
 Background information
 Study objectives
 Methodology
 Results
 Discussion and conclusion
 Acknowledgement
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Background information
 Development of new drugs, evaluation of drug-interactions
and therapeutic drug monitoring in individual patients require
pharmacokinetic analysis
 Pharmacokinetic sampling enables an accurate assessment
of the total exposure of the drugs.
 Saliva may be an easily obtainable alternative sampling
matrix for PK studies.
 salivary concentrations reflect the protein-unbound (active)
fraction of rifampicin in plasma.
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Study objectives
 To compare the PK of rifampicin in saliva and plasma
 To assess whether saliva could be an alternative matrix
for PK studies and TDM for rifampicin.
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Methodology
 Intensive pharmacokinetic sampling for INH, RIF, ETH
and PZA
 Time-matched samples of saliva and plasma
 Samples were taken at (t=0) and 1, 2, 3, 4, 6, 8, 10, 12,
and 24 hours.
 Plasma concentrations were quantified using validated
HPLC assays
 Pharmacokinetic parameters were determined using
WinNonlin Programme (version 5.2)
 All statistical analyses were done in SPSS, version
18.0
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Analysis
 Salivary, total (protein-unbound plus bound) and
unbound plasma concentrations of rifampicin were
measured.
 Performance of salivary concentrations to predict
plasma concentrations was evaluated.
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Results
 The geometric mean AUC0-24h of rifampicin in saliva
was 3.1 h*mg/L.
 Protein-unbound AUC0-24h in plasma was
5.3 h*mg/L
 AUC0-24h based on total concentrations (bound and
unbound was 32.7 h*mg/L.
 Corresponding geometric mean C max values were
0.64, 1.0 and 6.8 mg/L respectively.
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Pharmacokinetic of rifampicin in saliva and plasma (N= 15)
PK parameter
saliva
Plasma, proteinunbound conc.
Plasma, total
conc.
Ratio
saliva / plasma
protein-unbound
Ratio
Ratio
saliva / plasma total plasma proteinunbound / plasma
total
AUC0-24h (h*mg/L) 3.1 (0.70-8.6)
5.3 (1.8-10.3)
32.7 (11.7-73.6)
0.59 [0.50-0.71]
0.096 [0.077-0.119] 0.161 [0.146-0.178]
Cmax (mg/L)
0.64 (0.12-1.7)
1.0 (0.50-2.2)
6.8 (3.2-17.4)
0.62[0.42-0.91]
0.094 [0.063-0.140] 0.151 [0.136-0.167]
Tmax (h)
3.0 (1.0-6.1)
2.1 (1.0-6.0)
2.1 (1.0-6.0)
-
-
-
Cl/F (L/h)
164.1 (69.9-646.3)
97.6 (58.1-256.5)
15.7 (8.2-38.6)
1.68 [1.42-2.00]
10.4 [8.4-12.9]
6.21 [5.61-6.87]
Vd/F (L)
469.3 (223.3-1673.6) 318.8 (167.9-1022.4) 47.7 (24.4-139.5) 1.47 [1.26-1.72]
9.8 [8.1-11.9]
6.69 [5.69-7.85]
T1/2(h)
2.0 (1.3-2.7)
0.94 [0.84-1.06]
1.08 [0.96-1.21]
KCRI_PhD SYMPOSIUM 2013
2.3 (1.6-4.9)
2.1 (1.4-3.9)
0.88 [0.76-1.01]
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Results cont
 The prediction of total and unbound plasma
concentrations based on salivary concentrations of
rifampicin resulted in median percentage prediction
errors (MPPE) of 13.4% and 6.0%
 Measure of accuracy (<15%)
 Median absolute percentage prediction errors (MAPE)
was again 35.7% and 23.0%, respectively.
 Measure of precise (>15%).
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Discussion
 The salivary AUC0-24h and Cmax of rifampicin were much lower than
those in plasma
 This was anticipated, as only the protein-unbound (free) fraction of
a drug in plasma can pass into the salivary compartment.
 Several other factors that (apart from protein binding) determine
the extent of diffusion of drugs into saliva, including lipid solubility,
the degree of ionisation in blood and in saliva, and salivary flow
 The average protein binding of 84% which was found in this study
is close to 80% protein binding for rifampicin (Acocela G 1978, Holdiness 1984).
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Discussion cont
 The rifampicin molecule exhibits high lipid solubility
; its degree of ionisation is dependent on the pH
of the solution in which it resides.
[Kenny 1981]
 The rapid appearance of rifampicin in saliva suggest
that this TB drug enters saliva by passive diffusion
instead of active transport.
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Disc cont.
 Kenny and Strates 1981 stated that highest rifampicin levels
in saliva and sputum are obtained up to 4hr.
 Gurumuthy et al 1990 showed that peak concentrations of
rifampicin in saliva were 10.6% of those in plasma. Very
similar to data from our study (0.64mg/L to 6.8mg/L)
 Orisakwe et al 2004 found a much higher saliva to plasma
ratio for AUC0-24h (i.e. a ratio of 0.67). In our study it was
0.59.
 However in their study they used chewing gum stimulated
saliva and intensive pharmacokinetic sampling in healthy
volunteers.
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Conclusion
 The AUC0-24h of rifampicin in saliva was significantly
lower than the protein-unbound plasma AUC0-24h.
 Due to inadequate precision associated with this study
prediction, we can not advocate on the the use of saliva
as alternative matrix for TDM
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Acknowledgement
 Sponsoring programme:
APRIORI
 Kilimanjaro Clinical
Research Institute
 Kibong’oto National TB
Hospital (TZ)
 Radboud University
Nijmegen Medical Centre
(NL)
 Department of pharmacy
Radboud University (NL)
 Supervisors and TB team
members of KCRI/KNTH
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Ahsanteni sana
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