Approaches to handling missing or "problematic" pharmacology data: Pharmacokinetics.

Missing or erroneous information is a common problem in the analysis of pharmacokinetic (PK) data. This may present as missing or inaccurate dose level or dose time, drug concentrations below the analytical limit of quantification, missing sample times, or missing or incorrect covariate information. Several methods to handle problematic data have been evaluated, although no single, broad set of recommendations for commonly occurring errors has been published. In this tutorial, we review the existing literature and present the results of our simulation studies that evaluated common methods to handle known data errors to bridge the remaining gaps and expand on the existing knowledge. This tutorial is intended for any scientist analyzing a PK data set with missing or apparently erroneous data. The approaches described herein may also be useful for the analysis of nonclinical PK data.

Tenofovir Diphosphate Concentrations in Dried Blood Spots From Pregnant and Postpartum Adolescent and Young Women Receiving Daily Observed Pre-exposure Prophylaxis in Sub-Saharan Africa.

BACKGROUND: Intracellular tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is used to monitor cumulative pre-exposure prophylaxis (PrEP) adherence. We evaluated TFV-DP in DBSs following daily oral PrEP (emtricitabine 200 mg/tenofovir diphosphate 300 mg) among pregnant and postpartum adolescent girls and young women (AGYW). METHODS: Directly observed PrEP was administered for 12 weeks in a pregnancy (14-24 weeks' gestation, n = 20) and postpartum (6-12 weeks postpartum, n = 20) group of AGYW aged 16-24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography-tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated. RESULTS: Median age was 20 (IQR, 19-22) years. Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median (IQR) half-life was 10 (7-12) days in pregnancy and 17 (14-21) days postpartum, with steady state achieved by 5 and 8 weeks, respectively. Observed median (IQR) steady-state TFV-DP was 965 fmol/punch (691-1166) in pregnancy versus 1406 fmol/punch (1053-1859) postpartum (P = .006). Modeled median steady-state TFV-DP was 881 fmol/punch (667-1105) in pregnancy versus 1438 fmol/punch (1178-1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations. CONCLUSIONS: TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. These Population-specific benchmarks can be used to guide PrEP adherence support in pregnant/postpartum African women. CLINICAL TRIALS REGISTRATION: NCT03386578.

Individualized Adherence Benchmarks for HIV Pre-Exposure Prophylaxis.

Tenofovir diphosphate (TFV-DP) concentrations measured with dried blood spots (DBS) can be used to classify adherence to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV pre-exposure prophylaxis (PrEP). A TFV-DP of 700 fmol/punch was previously associated with high PrEP efficacy, and was estimated to represent ≥4 doses/week on average. However, interindividual variability in TFV-DP concentrations may lead to adherence misclassification and decrease the precision of adherence-efficacy relationships. The purpose of this analysis was to evaluate sources of TFV-DP variability to improve the precision of TFV-DP for adherence assessments by incorporating individual characteristics. Data and samples from a 36-week study of TFV-DP in DBS, collected biweekly, among 48 HIV-negative volunteers (25 Females/26 Caucasian/10 African American/14 Hispanic) receiving F/TDF at 33%, 67%, and 100% of daily dosing under directly observed therapy were used for analysis. The simplest pharmacokinetic model to describe TFV-DP accumulation with acceptable performance was a one-compartment constant input model. Covariates, including laboratory values and demographics were ranked in importance of their association with post hoc pharmacokinetic (PK) parameters using random forest analyses. Weight and platelet count were included in the final model and simulations were conducted to generate benchmarks for <2, 2-3, 4-5, and 6-7 doses/week. Based on these simulations, the previously established protective TFV-DP concentration of ≥700 fmol/punch was observed in those taking 2-3 (in individuals ≤110 kg) and ≥4 (in individuals >110 kg) doses/week, amounting to a much lower rate of misspecification (17% vs. 30%) with this individualized model versus previous interpretations. Incorporating body weight and platelet count improved the precision of TFV-DP concentrations for adherence assessments. Previous benchmarks were conservative, indicating that the pharmacological forgiveness of F/TDF may be higher than currently recognized and supports continued investigation of intermittent PrEP dosing regimens. Clinical Trial Registration number, NCT02022657.

Pharmacokinetics and renal safety of tenofovir alafenamide with boosted protease inhibitors and ledipasvir/sofosbuvir.

BACKGROUND: Ledipasvir/sofosbuvir increases tenofovir plasma exposures by up to 98% with tenofovir disoproxil fumarate (TDF), and exposures are highest with boosted PIs. There are currently no data on the combined use of the newer tenofovir prodrug, tenofovir alafenamide (TAF), boosted PIs and ledipasvir/sofosbuvir. OBJECTIVES: To compare the plasma and intracellular pharmacokinetics and renal safety of TAF with ledipasvir/sofosbuvir when co-administered with boosted PIs. METHODS: Persons with HIV between 18 and 70 years and on a boosted PI with TDF were eligible. The study was comprised of four phases: (1) TDF 300 mg with boosted PI; (2) TAF 25 mg with boosted PI; (3) TAF 25 mg with boosted PI and ledipasvir/sofosbuvir; and (4) TAF 25 mg with boosted PI. Pharmacokinetic sampling, urine biomarker collection [urine protein (UPCR), retinol binding protein (RBP) and ß2 microglobulin (ß2M) normalized to creatinine] and safety assessments occurred at the end of each phase. Plasma, PBMCs and dried blood spots were collected at each visit. RESULTS: Ten participants were enrolled. Plasma tenofovir exposures were 76% lower and tenofovir-diphosphate (TFV-DP) concentrations in PBMCs increased 9.9-fold following the switch to TAF. Neither of these measures significantly increased with ledipasvir/sofosbuvir co-administration, nor did TAF plasma concentrations. No significant changes in estimated glomerular filtration rate or UPCR occurred, but RBP:creatinine and ß2M:creatinine improved following the switch to TAF. CONCLUSIONS: Ledipasvir/sofosbuvir did not significantly increase plasma tenofovir or intracellular TFV-DP in PBMCs with TAF. These findings provide reassurance that the combination of TAF, boosted PIs and ledipasvir/sofosbuvir is safe in HIV/HCV-coinfected populations.

Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots Following Tenofovir Alafenamide: The TAF-DBS Study.

BACKGROUND: Tenofovir alafenamide (TAF), in combination with FTC, was recently approved for PrEP in the United States. The objective of this study was to assess the relationship between tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) with adherence to TAF/FTC. METHODS: TAF-DBS was a randomized, crossover clinical study of TFV-DP in DBS, following directly observed dosing of 33%, 67%, or 100% of daily TAF (25 mg)/FTC (200 mg). Healthy volunteers were randomized to 2 different, 12-week dosing regimens, separated by a 12-week washout. DBS were collected weekly. TFV-DP and FTC-TP were extracted from two 7-mm punches and assayed with LC-MS/MS. RESULTS: Thirty-seven participants (17 female, 7 African American, and 6 Hispanic) were included. TFV-DP exhibited a mean half-life of 20.8 days (95% confidence interval: 19.3 to 21.3). The slope for TFV-DP versus dosing arm was 1.14 (90% confidence interval: 1.07 to 1.21). The mean (SD) TFV-DP after 12 weeks was 657 (186), 1451 (501), and 2381 (601) fmol/2 7-mm punches for the 33%, 67%, and 100% arms. The following adherence interpretations are proposed: <450 fmol/punches, <2 doses/wk; 450-949 fmol/punches, 2-3 doses/wk; 950-1799 fmol/punches, 4-6 doses/wk; and ≥1800 fmol/punches, 7 doses/wk. FTC-TP was quantifiable for 1 week after drug cessation in 50%, 92%, and 100% of participants in the 33%, 67%, and 100% arms, respectively. CONCLUSION: TFV-DP in DBS after TAF/FTC exhibited a long half-life and was linearly associated with dosing, similar to its predecessor tenofovir disoproxil fumarate. FTC-TP was quantifiable for up to 1 week after drug cessation. Together, these moieties provide complementary measures of cumulative adherence and recent dosing for TAF/FTC.

Pharmacokinetics of tenofovir monoester and association with intracellular tenofovir diphosphate following single-dose tenofovir disoproxil fumarate.

BACKGROUND: Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported. METHODS: Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus® ingestible sensor. Plasma pharmacokinetics of tenofovir monoester and tenofovir were characterized using non-compartmental methods. Relationships with tenofovir diphosphate in DBS and PBMC were examined using mixed-effects models. RESULTS: Samples were available from 24 participants (13 female; 19 white, 3 black, 2 Hispanic). Tenofovir monoester appeared rapidly with a median (range) Tmax of 0.5 h (0.25-2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t½ of 26 min (31.0%). Tenofovir monoester Cmax was 131.6 ng/mL (69.8%) and AUC0-4 was 93.3 ng·h/mL (47.9%). The corresponding values for plasma tenofovir were 222.2 ng/mL (37.1%) and 448.1 ng·h/mL (30.0%). Tenofovir monoester AUC0-∞ (but not tenofovir AUC0-∞) was a significant predictor of tenofovir diphosphate in both PBMC (P = 0.015) and DBS (P = 0.005), increasing by 3.8% (95% CI 0.8%-6.8%) and 4.3% (95% CI 1.5%-7.2%), respectively, for every 10 ng·h/mL increase in tenofovir monoester. CONCLUSIONS: Tenofovir monoester Cmax and AUC0-4 were 59.2% and 20.6% of corresponding plasma tenofovir concentrations. Tenofovir monoester was significantly associated with intracellular tenofovir diphosphate concentrations in PBMC and DBS, whereas tenofovir concentrations were not. Tenofovir monoester likely facilitates cell loading, thereby increasing tenofovir diphosphate exposures in vivo.

Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients.

PURPOSE: The ability to predict and detect clinical and subclinical nephrotoxicity early in the course of therapy has the potential to improve long-term outcomes in cancer patients receiving cisplatin chemotherapy. Pharmacokinetic parameters could serve as predictors of cisplatin-induced nephrotoxicity. METHODS: Participants [n = 13] were treated with a 1-h cisplatin infusion [30-75 mg/m2]. Blood was collected pre-dose and up to 6 h post-dose. Urinary biomarkers [KIM-1, calbindin, clusterin, GST-pi, ß2M, albumin, NGAL, osteopontin, clusterin, MCP-1, cystatin C, and TFF3] were measured at baseline, days 3 and 10. Total and unbound platinum concentrations were measured using ICP/MS. Noncompartmental analysis was performed, and correlation and regression analyses evaluated the relationships between platinum pharmacokinetics and nephrotoxicity. RESULTS: Peak platinum urinary concentrations correlated with urinary levels of KIM-1, calbindin, clusterin, GST-pi, ß2M, albumin, NGAL, osteopontin, clusterin, cystatin C, and TFF3 at day 10. Unbound platinum plasma concentrations at 2 h also correlated with urinary clusterin, ß2M, cystatin C, NGAL, osteopontin, and TFF3 at day 3. Regression analyses suggested 2-h total plasma platinum concentrations greater than 2000 ng/ml, and peak urinary platinum concentrations above 24,000 ng/ml may serve as potential approximations for elevated risk of nephrotoxicity. Platinum area under the plasma concentration time curve was associated with serum creatinine and estimated glomerular filtration rate. CONCLUSIONS: Peak plasma and urinary platinum concentrations and pharmacokinetic parameters were associated with risk of subclinical cisplatin-induced kidney injury as assessed using novel urinary biomarkers. Future studies will examine these relationships in larger clinical populations of cisplatin-induced acute kidney injury.

Short Communication: Bioequivalence of Tenofovir and Emtricitabine After Coencapsulation with the Proteus Ingestible Sensor.

Adherence to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, Truvada®) is the primary determinant of HIV pre-exposure prophylaxis (PrEP) efficacy. Despite its importance, limitations exist in current methods of adherence quantification, restricting their implementation in the clinic. Proteus Discover (Proteus Digital Health®) can measure the time of each dose using an ingestible sensor that is coencapsulated with medication. In this study, the bioequivalence of coencapsulated TDF/FTC with the Proteus sensor was compared relative to unencapsulated drug. This was a 1:1 randomized cross-over study in which healthy participants received a single dose of unencapsulated and coencapsulated TDF/FTC. A 14-day washout separated each period. Blood was collected at predose and at 0.25, 0.5, 1, 2, 4, 6, 10, 24, 48, and 72 h postdose. Plasma concentrations were determined by LC-MS/MS methods, with a 10 ng/mL lower limit of quantitation (LLOQ) for both tenofovir (TFV) and FTC. Noncompartmental analysis was carried out with Phoenix® WinNonlin® for maximum concentrations (Cmax), area under the concentration-time curve from time 0 to the last measured time point (AUClast) and AUC extrapolated to infinity (AUCinf). Geometric mean ratios were calculated for each parameter and bioequivalence was defined as the 90% confidence interval (CI) of each ratio being within 80%-125%. Twenty-four participants (11 males; 19 white, 3 African American, and 2 Hispanic) completed both visits. Mean ± SD age was 28 ± 4 years and weight was 74 ± 14 kg. The 90% CIs for TFV Cmax, AUClast, and AUCinf were 89%-119%, 94%-111%, and 96%-111%, respectively. The 90% CIs for FTC Cmax, AUClast, and AUCinf were 96%-120%, 96%-108%, and 96%-108%, respectively. Bioequivalence was observed for the coencapsulation of TDF/FTC with the Proteus ingestible sensor, as assessed by a rigorously conducted pharmacokinetic study. Future studies will evaluate the utility and effectiveness of the sensor system as a tool to monitor PrEP adherence in clinical settings.