Clinical validation of a dried blood spot (DBS) method for the analysis of rifampicin (RIBOD study).

Both TB and NTM have a huge impact on world health. About 1/3 of the world
population is latently infected with TB. The highest burden of TB exists in
limited-resource countries, mostly in sub-Saharan Africa and Asia. NTM is
impacting world health more over the last two decades. Despite this high burden
and long experience with rifampicin, the optimal dose of rifampicin to
eradicate TB is still subject of ongoing investigation. The current standard
dose is 600 mg daily, though no clear evidence based on
pharmacokinetic/pharmacodynamic relationships exist. So future studies will be
performed on the optimal dosis, hereby investigating the pharmacokinetics of
TB.
Therapeutic drug monitoring (TDM) offers the possibility to individualize and
improve a patient*s pharmacological treatment, based on the measurement of drug
concentrations in biological samples. In clinical practice, TDM comprises the
measurement of one or more drug concentrations associated with the
administration of the dose of a certain drug. Dependent on the drug exposure
measured, the dose of the drug may be increased or decreased. This is expected
to result in a change in exposure, which in turn may yield more efficacy or
less toxicity. In this way, the aim of TDM is to improve exposure aiming at
maximizing efficacy and minimizing toxicity for an individual patient. TDM is
often peformed in patients treated with rifampicin.
Conventionally, TDM is performed with blood or plasma obtained by venous blood
sampling. This method is associated with several challenges such as i) the need
for the patient to travel to the hospital or health center; ii) special
conditions for sample transport to guarantee stability of the analyte and to
decrease the biohazard risk; iii) sampling times not always representing the
preferable peak or trough concentrations; iv) the method being invasive and v)
delay of the outcome of the analyses with regard to the outpatient visit.
The Dried Blood Spot (DBS) may offer a solution for all these challenges. To
perform the DBS technique, only a small amount of blood is needed and this
sample can easily be obtained via a finger prick is put on a piece of filter
paper, can be taken at home and is sent to the laboratory by post mail.
Patients or their caregivers can perform the sampling at the appropriate time
in the concentration curve, e.g. at the time of the trough concentration, while
avoiding an extra visit to the hospital or health center. When arriving at the
hospital for a meet-up with the physician, adaptation of the dose based on the
already available drug concentration is directly possible and a delay
introduced by conventional sampling procedures is thereby avoided

In addition to TDM of rifampicin, also PK research with this drug is thought to
benefit from DBS. DBS is thought to offer benefits especially for the
performance of PK studies in remote areas and limited-resource countries with a
tropical climate. The cold chain required for conventional blood sampling is
generally not required with DBS. Moreover, as PK studies and dose-finding
regimes should be carried out in each target population, most of research is to
take place in Asia and Africa.

In an earlier study (PROTECT) from the hospital pharmacy of the Radboudumc, a
similar approach was used and approved by the local ethics committee (Commissie
Mensgebonden Onderzoek, CMO regio Arnhem-Nijmegen).

Primairy
To clinically validate a finger prick DBS method compared to conventional
venous sampling for the analysis of rifampicin.

Secondairy
* Feasibility of the novel finger prick DBS method in the target population
will be assessed. This includes scoring of relevant characteristics
(attributes) of blood drawing methods for TDM, evaluation of the experience and
attitude of the patients regarding finger prick DBS sampling and evaluation of
the understanding of the written instructions provided for performing the
finger prick at home. The data obtained in this validation study will be used
for the implementation of the DBS in therapeutic drug monitoring (TDM) being a
less invasive procedure, for DBS as a method of blood drawing in futuer PK
studies and as a base for a discrete choice-experiment as part of the HTA.
* To design an inventory of types of costs that will be incurred in the process
of DBS-based and conventional TDM as a
preparation step for later health economic analysis.

This is an observational single-centre study in which DBS sampling is compared
with conventional sampling for concentration measurment of rifampicin. The
concentration of rifampicin will be determined in dried blood spots obtained by
a finger prick and in plasma obtained by simultaneous venous sampling in a tube
of blood. Statistical analysis will be deployed to assess the association of
the concentrations obtained with both methods of blood drawing. Also, the
predictive performance of the DBS method will be assessed (for details on the
statistical analysis we kindly refer to chapter 8 of the protocol).

As in this study no change in therapy is performed it possesses a minimal risk.
The risks associated with a finger prick are
pain at the puncture site and risk of bleeding. We will actively assess those
factors during the study. The risks associated with venous blood sampling are
similar (e.g., risk of infection, risk of hematomas and pain and/or discomfort
at the puncture site). Venous blood will be drawn as much as possible from a
central venous catheter (CVC or PAC), that will be placed in the vene. Only
experienced personnel will perform the study.