Background/Aims: Hereditary spherocytosis (HS) is a common pediatric hemolytic anemia caused by congenital red blood cell defects. HS due to ankyrin 1 (ANK1) mutations is the most common type. We explored an ANK1 mutation from an HS patient and reviewed the literature. Methods: We detected the mutation in a Chinese family in which 2 members were diagnosed with HS by next-generation sequencing. The proband was diagnosed with HS in the newborn period, based on clinical manifestations, laboratory data, and family history. The mutation spectrum of the ANK1 gene was summarized based on 85 patients diagnosed with HS carrying ANK1 mutations, and the ANK1 mutation spectrum was summarized and analyzed. Results: We identified a novel mutation affecting ANK1 gene splicing (a splicing mutation) in both the patient and her mother, which is a substitution of T>G 2 nt after exon 25 in intron 26. The study expands our knowledge of the ANK1 gene mutation spectrum, providing a molecular basis for HS. Conclusion: A novel ANK1 mutation (NM_000037.3, c.2960+2T>G, intron 26) that is potentially associated with HS was identified. To date, 80 ANK1 mutations have been reported to be associated with HS in humans.
Introduction
HS-10234, a novel prodrug of tenofovir (TFV), functions by inhibiting nucleotide reverse transcriptase against retroviral infections including hepatitis B virus and human immunodeficiency virus (HIV). As it is a possible substitute for TFV co-administration with emtricitabine, determining the drug-drug interactions (DDI) between HS-10234 and emtricitabine therapy will be helpful for researchers to design and conduct future phase II/III studies and merits careful examination in the era of evolving new combination antiretroviral therapy regimens.
Methods
We conducted an open-label, two-sequence, two-period, self-controlled phase I trial that enrolled 36 healthy volunteers randomized into two groups (group 1 and group 2). Eighteen subjects in group 1 were orally administered HS-10234 at a 25-mg daily dose for 7 days during period 1 (D1–D7) followed by co-administration of emtricitabine at a 200-mg dose once daily (QD) for 7 additional days during period 2 (D8–D14). Participants in group 2 were orally administered emtricitabine 200 mg QD for 7 days during period 1 (D1–D7) and then co-administered HS-10234 25 mg QD for 7 additional days during period 2 (D8–D14). Pharmacokinetics (PK) of HS-10234 and emtricitabine were characterized when administered alone and in combination. The concentrations of HS-10234 and its metabolites TFV and emtricitabine were determined using high performance liquid chromatography-mass spectrometry (HPLC-MS)/MS. Peripheral blood monocyte cells (PBMCs) were isolated for detection of intracellular concentrations of HS-10234’s active metabolite, intracellular tenofovir diphosphate (TFV-DP) pre-dose and 2, 4, 8, 12 and 24 h post-dose on D7 and D14 in group 1. WinNonlin software was used to calculate PK parameters.
Results
After multiple-dose administration of HS-10234 with emtricitabine, the AUC
0–tau
of HS-10234 and TFV-DP was 1.327- and 1.403-fold higher than that with HS-10234 administration alone. The
C
max
and AUC
0–tau
were increased 1.120- and 1.077-fold compared to emtricitabine administration alone. Co-administration of HS-10234 with oral emtricitabine was well tolerated. No serious adverse events were observed.
Conclusions
Although a slightly increased steady-state PK exposure of HS-10234 and TFV-DP was observed with co-administration of oral HS-10234 with emtricitabine, these changes were not considered clinically relevant. Thus, dose adjustments are not recommended for HS-10234 combination with emtricitabine.
Trial Registration
NCT04477096, July 20, 2020.
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