Dosing Regimen for Tenofovir Pharmacokinetics

Subjects were randomly assigned to one of 6 dosing sequences and completed three 6-week dosing periods of 2, 4 and 7 doses per week, with a break of at least 3 weeks between periods (Figures 1 and 2). Based on an average hair growth rate of 1 centimeter per month [30] (link), a minimum of 3-weeks was chosen for the washout period. Each sequence arm included both sexes equally for a total of 12 male and 12 female participants. The 2 doses/week were taken on Tuesday and Wednesday, and the 4 doses/week on Monday, Tuesday, Thursday, and Friday. All scheduled doses on Monday to Friday were directly observed by study staff, and weekend doses were confirmed by text messaging or phone using previously-described mDOT procedures [31] (link), [32] . A one-week supply of back-up medication was provided for participants unable to complete a directly-observed dose; these doses were confirmed via phone or text message at dosing. Dosing visits occurred at UCSF, SFDPH, or another location per participant convenience. Participants returned to the clinic for follow-up at a start, mid-point (after 3 weeks of dosing), and end-point (at the end of each 6 week dosing period) visit for safety and adverse event monitoring, symptom-directed physical exams, and rapid HIV testing.
At enrollment and end-point visits, approximately 150–200 strands of scalp hair were collected; additionally, a similar number pubic hair strands were collected on an opt-in basis. After 4 weeks of dosing during the 7 doses/week period (at steady state for plasma TFV), participants were admitted to the UCSF Clinical Research Center for intensive 24-hour plasma PK evaluations to calculate individual PK parameters (plasma AUC for oral clearance and C_max). The participant's usual diet was ascertained prior to the PK visit, and simulation of the usual diet was undertaken during PK sampling. An initial blood level was drawn (called the “0” timepoint) prior to an observed dose of TFV, followed by blood collection at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post-dose for measurement of TFV plasma concentration. Concentrations could not be measured for one participant at the 0.5 hour time and another participant at the 1.5 hour time; these were interpolated by fitting quadratic functions to the log-concentrations using the two previous and two subsequent times.