A New Oral Testosterone Undecanoate Formulation Restores Testosterone to Normal Concentrations in Hypogonadal Men

Ronald S. Swerdloff; Christina Wang; William B. White; Jed Kaminetsky; Marc C. Gittelman; James A. Longstreth; Robert E. Dudley; Theodore M. Danoff

Disclosures

J Clin Endocrinol Metab. 2020;105(8) 

In This Article

Results

Subject Disposition and Baseline Characteristics

A total of 221 eligible patients were randomized and received treatment in a 3:1 ratio to oral TU (JATENZO®; N = 166) or topical T (Axiron®; N = 55). Approximately 92% of the patients who were randomized to oral TU completed the study compared to 88% in the topical T arm. Figure 1 summarizes the overall subject disposition by treatment group for the intent-to-treat population. Demographics and baseline characteristics were similar between the two treatment arms as summarized in Table 1.

Figure 1.

Overall subject disposition by treatment group for intent-to-treat pharmacokinetics (PK) populations.

Efficacy Results

Primary and secondary efficacy results are summarized in Table 2. Based on T results obtained at the final PK visit of the study, 87.3% of patients in the oral TU group had T Cavg values in the eugonadal range, with a mean ± SD value of 403 ± 128 ng/dL (14 ± 4 nmol/L) based on T assay of NaF-EDTA plasma. When expressed in terms of approximate equivalent serum T concentration,[15] the mean ± SD value was 489 ± 155 ng/dL (17 ± 5 nmol/L). Of those patients dosed with topical T, primary efficacy identical to oral TU was observed (i.e., 87.3%) based on final visit T assays. Sensitivity analyses [i.e., last-observation-carry-forward (LOCF), multiple imputation and imputation from baseline] were performed to assess the impact of missing T data at the final PK visit for oral TU patients. All three analyses resulted in estimates of the percentage of patients in the eugonadal T range of 86 to 90%.

At the end of the study, values of T Cmax ≤1500 ng/dL were observed for 90.7% of patients in the oral TU group and 97.9% of patients in the topical T group. None of the patients treated with oral TU experienced a Cmax value >2500 ng/dL except for three spurious and transient Cmax excursions above 2500 ng/dL that were determined to be the result of external contamination of the 2-hour post-dose plasma samples at a single study site where plasma samples were being prepared from topical T patients at the same time as samples from those dosed with oral TU. If a blood sample collected from an oral TU-treated subject was contaminated with exogenous T, the expectation was that the T concentration in the sample would be enhanced but the DHT concentration would not be. And this was found to be true. The DHT/T molar ratios for the three suspect samples where all were between 0.0439 and 0.0602, values that were less than half the mean DHT/T ratio (0.1484) observed in 2-hour post-dose samples of the other oral TU-treated subjects.

Effects on Sexual Function and Mood

As illustrated in Figure 2, both the oral TU and topical T groups demonstrated significant improvements from baseline (p < 0.0001) in each of the psychosexual parameters, with mean increases from baseline noted for sexual desire, sexual enjoyment with and without a partner, sexual activity, satisfaction with erection duration, % full erection, and positive mood and mean decreases noted for negative mood. No significant differences in magnitude of change from baseline between the treatment groups (p > 0.05 for all comparisons) were observed for any of the Psychosexual Daily Questionnaire parameters.

Figure 2.

Effects of oral TU and topical T on mean change from baseline in Psychosexual Daily Questionnaire data at end of study (all T-treated patients). *Statistically signficant difference from baseline (P < 0.0001).

Oral TU Dose Titration and Pharmacokinetics

The average dose of oral TU increased with each titration cycle. Overall, there were more up-titrations than down-titrations. Among the 155 oral TU patients who completed the study, approximately 72% were up-titrated from the initial dose (32% to 316 mg and 40% to 396 mg TU, BID), 26% remained at their initial oral dose of 237 mg TU, BID, and 3% were down-titrated (237 to 198 mg TU, BID). Among the 49 topical T patients who completed the study, approximately 45% required no titration from the initial dose of 60 mg QD, while the remaining patients were titrated up in dose.

The average dose of oral TU progressively increased during the titration process from the starting dose of 237 mg oral TU, BID to 287 mg TU in response to dose adjustments made at the first titration visit to 325.1 mg TU after dose adjustments were made at the second (and final) titration step. Upward adjustments to oral TU dose were consistent with the increases in the mean T concentration-time profiles across the three different visits. Mean concentration-time profile for NaF-EDTA plasma total T at the PK visits is shown in Figure 3 for the oral TU patients.

Figure 3.

Mean (±standard error) concentration-time profiles for NaF-EDTA plasma total T in patients treated with oral TU at the first, second, and final pharmacokinetics (PK) visit. Values in graphs can be converted to approximate serum T equivalents by multiplying by 1.214 (see text for detail). *As measured in NaF-EDTA plasma.

When the T results of all patients at a particular visit were combined, regardless of the dose of oral TU they received, the mean peak T over 24 hrs. (Cmax24) for oral TU patients ranged from approximately 800 ng/dL at the first dose titration to 1000 ng/dL at the end of study and occurred at median times of approximately 2–4 hours following the AM dose, and approximately 4 hours following the PM dose. The mean NaF-EDTA plasma (approximate equivalent serum T) Cavg24 values ranged from 335 (407) ng/dL at the first titration to 403(489) ng/dL at the final PK visit. The coefficients of variation (CVs) for Cavg24 decreased as the visits progressed through the study (46.7% to 37.7% to 31.7%), as would be expected since the titration process was designed to down titrate those patients with high Cavg24 values and up titrate patients with low Cavg24 values, thus progressively narrowing the distribution of Cavg24 values with each titration step. The outcome of this process is depicted graphically in Figure 3. The mean plasma total T PK parameters at the end of study are summarized by treatment for all doses combined in Table 3.

Single-sample Dose-adjustment Paradigm for Oral TU

Pharmacokinetic (PK) modeling and simulation results for circulating T confirmed that dose titration decisions based on a single blood sample taken 3–5 hours or at 4 hours after the morning oral TU dose was an effective means to guide dose adjust to achieve/maintain T concentrations in the eugonadal range. As shown in Table 4 regardless of the three measures used to determine the need to adjust the oral TU dose (i.e., Cavg based on serial PK blood sampling, a single blood sample 4 hours after the morning dose or a single sample taken any time between 3 to 5 hours after oral TU), efficacy was high with 95% of patients achieving a mean T concentration in the eugonadal range and <5% of patients with a mean T level below normal. Concordance analysis of the results from the first and second dose-titration visits are shown in Figure 4 [tabular concordance data are available in Dryad Digital Repository[23]]. These results demonstrated that for the first and second PK visits, total concordance was 88% and 93%, respectively, when a single blood sample for T assay was collected 4 hours after the oral TU dose. When total concordance was analyzed on the basis of a single T concentration at 6 hours after oral TU at the first and second PK visit, total concordance was 98 and 96%, respectively.

Figure 4.

Concordance between decision to adjust oral TU dose on basis of single sample determination of circulating T concentration at 4 and 6 h after the morning oral TU dose and outcome of decision for first and second dose-titration cycles.

Derivation of a Conversion Factor to Permit use of Serum v. NaF-EDTA Plasma T to Guide Dose Adjustments in Men Treated with Oral TU in a Clinical Setting

As noted previously, in order to monitor T levels in patients receiving oral TU using standard blood collection techniques (i.e., plain tube for serum T assay), it was necessary to derive a conversion factor which accounted for TU-to-T conversion in serum from blood that had clotted at room temperature v. NaF-EDTA blood collection tubes held on ice that prevented this conversion (i.e., blood collection method as used in current Phase 3 clinical trial). We have shown previously that the amount of T generated due to TU-to-T conversion is, in part, a function of TU concentration and that NaF directly decreased T levels assayed by LC/MS-MS when blood was collected into NaF containing tubes.[15] Thus, we were able to calculate a conversion factor based on the regression equations or the estimated TU concentration 6 hours post-dose, namely, 52 ng/mL (obtained from a non-published study; ClinicalTrials.gov Identifier: NCT01403116). To convert a T concentration measured in NaF-EDTA plasma to an equivalent T concentration measured at C6 in serum required multiplying the NaF-EDTA plasma T concentration by 1.214. This overall correction factor is the product of three independent factors: 0.999 (to account for the small amount of overestimation in the NaF-EDTA containing tube) x 1.043 (to account for the overestimation of T that would occur in the plain tube due to TU to T conversion) x 1.166 [to account for a NaF matrix effect (NaF-EDTA plasma v. serum)] on T measurement.[15] Thus, it was possible to obtain a close estimation of the equivalent serum T concentration in samples collected 6 hours post-dose when the T concentration was measured in NaF-EDTA plasma. To test the applicability of this conversion factor (derived from the N = 13 blood collection study), it was applied to NaF-EDTA plasma T data generated from oral TU patients at their final PK visit. At that visit, duplicate PK samples were collected in NaF-EDTA and plain tubes so T concentrations could be measured in both. Applying the conversion factor resulted in a mean (95% CI) error of only 3.1% (0.4%, 5.8%)—too small to impact essentially any dose titration decision. Furthermore, this error is substantially less than the 15% error allowed for most clinical assays.[24] Finally, this conversion factor was integrated (invisibly) into product labeling for the new oral TU formulation such that health care providers can assess T response and make dose-titration decisions based on serum T derived from blood collected into standard plain tubes (i.e., devoid of any chemicals).

Food Effect

There was no clinically significant difference in dose-normalized T Cavg among the meal types, indicating that dose titration based on post-AM blood samples was not significantly impacted by the AM meal fat composition between 15 to 45 g fat (see Figure 5). There was also no significant effect of food on peak T (Cmax) concentrations. These data demonstrate the reproducibility of PK responses of patients on a particular diet (i.e., with respect to fat content) over the PK visits, regardless of their oral TU dose. Dose normalization compensates for any dose titration changes between PK visits. The PK patterns were similar with both the AM and PM doses and even though the high fat and very low fat patients had the most variability in the between visit PK values, they were not substantially different between visits, nor substantially different from patients on diets with other fat content.

Figure 5.

Dose-normalized mean average T concentration (Cavg) at PK visits for oral TU patients (stratified by mean dietary fat content).

Changes in Calculated Free T, SHBG, Estradiol, DHT, LH and FSH After Oral TU

Effects of oral TU and topical Ton calculated free T, DHT, estradiol (E2), LH, FSH and SHBG are depicted in Figure 6. As expected in both treatment groups, T administration caused significant elevations from baseline in free T, DHT, and estradiol and decreases in, LH, FSH and SHBG. The magnitude of effects observed in oral TU patients paralleled those seen in patients treated with topical T and the differences in responses between the treatment groups was not statistically different. However, there was a trend toward higher free T concentrations in oral TU patients compared to topical T patients and a greater mean decline in SHBG in oral TU patients. The greater increase in free T from baseline for the oral TU group was partly a function of a 36% decrease in mean SHBG from 28.6 ± 14.7(SD) to 17.0 ±7.6 nmol/L in the oral TU group compared to essentially no change in the topical T group from 26.8 ± 10 to 26.4 ± 11.7 nmol/L. However, both baseline and final mean SHBG concentrations remained within the normal range for eugonadal men (10.8 to 46.6 nmol/L) at the final study visit in both groups.

Figure 6.

Effect of oral TU and topical T on LH, Free T, DHT, FSH, estradiol, and SHBG over course of T therapy.

Over the course of the study, mean estradiol levels increased to slightly above the upper end of the eugonadal range in both treatment groups [oral TU: 32 ± 14 pg/mL (117 ± 51 pmol/L) and topical T: 33 ± 18 pg/mL (121 ± 66 pmol/L]. Plasma DHT concentrations for the oral TU- and topical T treated patients were essentially identical at all PK visits and at the final visit [73 ng/dL (2.5 nmol/L) were slightly above the normal upper limit of 65 ng/dL (2.2 nmol/L). Mean change from baseline in the serum concentrations of LH and FSH at end of study (AM pre-dose concentration) in the oral TU and topical T patients showed an approximately 70% decrease from mean baseline values.

Safety Results

The overall incidence of treatment-emergent adverse events (TEAEs) considered related to study drug occurred in 18.7% of patients in the oral TU group and in 14.5% of the topical T group (Table 5). No deaths occurred during the study, and there were no drug-related serious adverse events. The proportion of patients who prematurely discontinued from the study due to adverse events was 1.8% in each treatment group. Changes from baseline to final visit in several important clinical chemistry, hematology and hemodynamic parameters of interest in men treated with T are summarized in Table 6.

Investigator-reported TEAEs which occurred more frequently in oral TU patients than in the topical T group were increased hematocrit, hypertension, and decreased high-density lipoprotein (HDL). Each of these events (occurring in 3–5% of oral TU patients) was reported as mild or moderate in intensity and none resulted in premature discontinuation from the study. Decreased HDL events occurred at the higher oral TU doses (316 mg and 396 mg BID), whereas events of increased hematocrit and hypertension were not related to TU dose.

As expected, based on the pharmacological actions of T, mean increases from baseline in hematocrit were observed in both treatment groups at each study visit but remained within the normal range in most men (97% oral TU; 100% topical T). Shifts from normal hematocrit values at baseline to above the normal range were observed in 3% of oral TU patients at the final visit, compared with none of the topical T patients.

No clinically significant changes in the liver function tests [i.e., alanine (ALT) and aspartate (AST) aminotransferases, alkaline phosphatase (AP) and bilirubin] were observed in either treatment group (Table 6). Two oral TU patients experienced increases in AST or ALT that were < 2x the upper normal limit (UNL) and one oral TU patient experienced a transient elevation of AST (<2x UNL) that returned to normal during continued oral TU therapy. Changes in lipid profiles were more pronounced among oral TU patients compared with topical T patients. Shifts from normal baseline to below the normal range for HDL were observed in 28.9% of oral TU patients compared with 14.8% of topical T patients at the final visit. Smaller differences between the treatment groups were observed for shifts from normal baseline to above the normal range in total cholesterol (7.8% versus 3.7%) and triglycerides (13.3% versus 9.3%).

Clinic systolic BP (i.e., cuff) increased from baseline to the end of the study (final visit) in both treatment groups (mean ± SD: oral TU, 2.8 ± 11.8 mm Hg; topical T, 1.8 ± 10.8 mm Hg), whereas diastolic blood pressure was essentially unchanged at the final visit for both groups. Censoring measurements collected after addition of or an increase in dosage of antihypertensive medications had little effect on estimates of mean change for clinic BP. The changes from baseline in systolic BP for the treatment groups were considered in the context of the 2017 AHA/ACC BP classifications (Table 7). The baseline BP was higher in the oral TU group as evidenced by the greater percentage of patients with Stage 1 or 2 hypertension in the oral TU group than in the topical T group, 65% vs 42%, respectively. Testosterone treatment induced a shift to higher BP classifications, but shifts to Stage 1 or 2 hypertension were similar in both treatment groups (31% of the oral TU and 32% of the topical T group).

Measurement of BP with ABPM yielded greater mean increases from baseline to end of study (approximately 2 days prior to final PK visit) in average daytime (P < 0.01), nighttime (P < 0.01), and 24-hour (P < 0.002) systolic BP for the oral TU group than for the topical T group. The 24-hour average systolic BP increased 4.9 ± 8.7 mm Hg in the oral TU group and 0.2 ± 9.4 mm Hg in the topical T group (P = 0.0013). Mean increases in the average daytime, nighttime, and 24-hour diastolic BP from baseline to Visit 6 for the oral TU group were also greater than for the topical T group but the differences were not statistically significant. Among the oral TU patients, mean increases in systolic BP were slightly greater in patients with a history of hypertension who were receiving antihypertensive medication (5.5 ± 8.9 (SD) mm Hg) compared to those with no history of hypertension (4.3 ± 8.6 (SD) mm Hg). There were no discontinuations of oral TU due to hypertension; 5.9% of oral TU patients initiated antihypertensive medication or required a dose increase of existing therapy. The 24-hour average heart rate in the oral TU treated group increased by 2.2 ± 7.7 (SD) beats/minute while in the topical T treated group heart rate decreased by 0.1 ± 6.3 bpm. The changes in heart rate were not statistically significant in either treatment group.

Mean and median changes in PSA were small and comparable between the treatment groups. In addition, a statistically significant difference was not observed between the treatment groups for the proportion of patients with PSA values > 4 ng/mL or with a change from baseline > 1.4 ng/mL at the end of study (1.9% oral TU; 3.8% topical T). Consistent with the PSA data, only minimal and clinically insignificant effects were observed in both treatment groups for urinary symptoms measured by I-PSS.

The cosyntropin stimulation sub-study was included to evaluate the effect of oral TU on cortisol production due to findings of adrenal cortex atrophy and reduced cortisol levels in dogs treated with high doses of oral TU. Although the oral TU group had a significantly lower proportion of patients who had a post-cosyntropin stimulation cortisol value ≥ 18 μg/dL than the topical T group (79% v. 100%), the differences between Day 1 and final study day for maximum cortisol concentrations post-injection and changes in cortisol concentrations from pre-injection showed no statistically significant differences between the treatment groups. Four oral TU patients had cortisol values after cosyntropin stimulation that were slightly below the response cutoff level of 18 μg/dL; however, these responses in cortisol levels (range: 16.5 to 17.6 μg/dL) were not consistent with adrenal insufficiency and not considered clinically significant. Notably, during T treatments (and similar to SHBG levels), cortisol binding globulin levels were suppressed in the oral TU group compared to the topical T group such that when free cortisol levels were calculated, there was no difference the two groups. Only 2 patients had post-stimulation free-cortisol values that were minimally below the published threshold for free cortisol of 1.19 μg/dL.[25]

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