SALIVARY, PROTEIN UNBOUND AND TOTAL PLASMA CONC OF RIFAMPICIN HADIJA H SEMVUA 11/12/2015KCRI_PhD SYMPOSIUM 2013 1

SALIVARY, PROTEIN UNBOUND AND TOTAL

PLASMA CONC OF RIFAMPICIN

HADIJA H SEMVUA

04/20/23KCRI_PhD SYMPOSIUM 2013 1

Outline Background information

Study objectives

Methodology

Results

Discussion and conclusion

Acknowledgement


Background informationDevelopment 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.

04/20/23 3KCRI_PhD SYMPOSIUM 2013

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.


MethodologyIntensive 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



AnalysisSalivary, total (protein-unbound plus bound) and

unbound plasma concentrations of rifampicin were measured.

Performance of salivary concentrations to predict plasma concentrations was evaluated.


ResultsThe 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.


Pharmacokinetic of rifampicin in saliva and plasma (N= 15)


Results contThe 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%).


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).


Discussion contThe rifampicin molecule exhibits high lipid

solubility [Kenny 1981]; its degree of ionisation is dependent on the pH of the solution in which it resides.

The rapid appearance of rifampicin in saliva suggest that this TB drug enters saliva by passive diffusion instead of active transport.


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.


ConclusionThe 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


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


Ahsanteni sana


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SALIVARY, PROTEIN UNBOUND AND TOTAL PLASMA CONC OF RIFAMPICIN HADIJA H SEMVUA 11/12/2015KCRI_PhD SYMPOSIUM 2013 1