Background: Directly Observed Therapy (DOT) is universally recommended for TB treatment adherence, but DOT is resource intensive, expensive and unfeasible in resource-limited settings. Novel WOT technology provides date- & time-stamped recording of medication ingestions via an ingestible sensor and monitor patch worn on the patient’s torso. Ingestion data is transmitted to a paired mobile device and then uploaded to a secure Internet server, where healthcare workers can confirm ingestions remotely.
Methods: We integrated the ingestible sensor (IS) with Rifamate and Rifinah, the combination dosage forms of isoniazid (INH) and rifampin (RIF), via over-encapsulation (OE) with Gelcaps. We performed dissolution testing on these. We conducted a randomized bioequivalence (BE) study in 12 patients with active TB during the continuation phase comparing ISRifamate to its native form. INH and RIF were assayed using validated HPLC methods, and the pharmacokinetic parameters were analyzed using non-compartmental methods (Phoenix/WinNonlin software). We measured the positive detection accuracy (PDA) of the WOT system using ISRifamate by comparing WOT ingestions recorded when doses were given under DOT (n=280) and evaluated WOT performance in comparison to DOT in 14 active TB patients.
Results: Patients mean age was 41 yrs, 71% male. Dissolution of OE ISRifinah 100mg/300mg was 100% at 43-45 mins for RIF and INH, meeting USP requirements. Dissolution for OE ISRifamate (100mg/300mg) reached 85-90% at 120mins. In the PK analysis of OE ISRifamate versus native form, INH and RIF were bioequivalent using the population method ratio test (95% confidence level); median INH Cmax were 3.85 and 4.27 mcg/ml; median AUC0-12h were 13.34 and 12.50 mcg/ml for native and OE, respectively. Median RIF Cmax were 12.12 and 11.79 mcg/ml; median AUC0-12h were 45.19 and 43.76 mcg/ml for native and OE ISRifamate, respectively. PDA for WOT based on 280 simultaneous DOT ingestions was 98.7% (mean), 100% (median), range (94-100%). However, the total number of WOT observations versus the total numbers of DOT doses was 148% (mean), 142% (median), range (130-187). Patients found the system easy to use with 90% giving high comfort ratings; 1 transient skin rash was observed.
Conclusions: Over–encapsulation with IS was safe and bioequivalent to standard drug. The PDA confirms WOT is highly accurate. WOT is delivered daily and confirmed more drug doses ingested than DOT overall. WOT represents a new paradigm in TB therapy monitoring.